Somatic and germline mutations in the pathogenesis of pituitary adenomas

in European Journal of Endocrinology
Authors:
Silvia VandevaDepartment of Endocrinology, Specialized Hospital for Active Treatment of Endocrinology, Medical University, Sofia, Bulgaria

Search for other papers by Silvia Vandeva in
Current site
Google Scholar
PubMedClose
,
Adrian F DalyDepartment of Endocrinology, Centre Hospitalaire Universitaire de Liège, Liège Université, Liège, Belgium

Search for other papers by Adrian F Daly in
Current site
Google Scholar
PubMedClose
,
Patrick PetrossiansDepartment of Endocrinology, Centre Hospitalaire Universitaire de Liège, Liège Université, Liège, Belgium

Search for other papers by Patrick Petrossians in
Current site
Google Scholar
PubMedClose
,
Sabina ZacharievaDepartment of Endocrinology, Specialized Hospital for Active Treatment of Endocrinology, Medical University, Sofia, Bulgaria

Search for other papers by Sabina Zacharieva in
Current site
Google Scholar
PubMedClose
, and
Albert BeckersDepartment of Endocrinology, Centre Hospitalaire Universitaire de Liège, Liège Université, Liège, Belgium

Search for other papers by Albert Beckers in
Current site
Google Scholar
PubMedClose
View More View Less

Correspondence should be addressed to A Beckers; Email: albert.beckers@chuliege.be
DOI:
https://doi.org/10.1530/EJE-19-0602
Volume/Issue:
Volume 181: Issue 6
Page Range:
R235–R254
Article Type:
Review Article
Online Publication Date:
Dec 2019
Copyright:
© 2019 European Society of Endocrinology 2019
Free access

Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

Abstract

Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

Introduction

Pituitary adenomas are benign neoplasms that are found in up to 20% of pituitaries on MRI or autopsy (1), while clinically relevant pituitary adenomas occur in approximately 1:1000 people (2). Usually they are monoclonal in origin, expanding from molecular genetic abnormalities in a single somatic cell (3). However, there is evidence demonstrating that pituitary adenomas could be polyclonal, especially recurrent tumors (4). Tumorigenesis involves differential expression of tumor suppressor genes and oncogenes, hormones and growth factors and their receptors, adhesion molecules and microRNAs that lead to disruption of the cell cycle and abnormalities in various signal transduction pathways (5, 6, 7, 8, 9). Often, however, the initial trigger of the tumorigenic cascade remains largely unknown. In the last decade significant progress has been made with the discovery of several genetic defects implicated in pituitary tumor pathogenesis in previously recognized or new clinical conditions. Among these newer genetic discoveries are germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene that were found in familial and sporadic pituitary adenomas (10, 11). Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants were ascribed to a MEN1-like condition, known as MEN4 syndrome (12). Xq26.3 duplications involving the gene GPR101 have been demonstrated in X-linked acrogigantism (X-LAG) (13). The 3P (pheochromocytoma and/or paraganglioma, and pituitary adenoma) association (3PAs) is related to pathogenic variants of the succinate dehydrogenase complex genes, among others, and suggests that pheochromocytoma/paraganglioma-related genes might rarely cause pituitary adenomas (14, 15). Many adenomas arising in the context of germline pathogenic variants or syndromic conditions have an aggressive clinical behavior and show poor responses to standard treatments. However, the prevalence of known germline pathogenic variants in the overall pool of unselected sporadic adenomas is still low (9, 11). Regarding somatic pathogenic variants, until recently, only stimulatory guanine nucleotide (GTP)-binding protein alpha (GNAS) pathogenic variants were known to be causally related to somatotropinoma pathogenesis in a sizeable proportion of cases (16, 17). Current genomic techniques allowed the identification of other frequently recurrent somatic genetic alterations – phosphatidylinositol 3 kinase alpha subunit (PIK3AC) gene in various types of pituitary adenomas (18, 19) and ubiquitin-specific protease 8 (USP8) (20, 21) and USP48 gene pathogenic variants in corticotropinomas (22).

Somatic mutations in pituitary adenomas

GNAS mutations

The deregulation of the cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway is strongly implicated in pituitary tumor pathogenesis through different PKA-dependent and -independent mechanisms, which together lead to hormonal hypersecretion and cell cycle disruption (6, 23, 24). One of the most common somatic disruptions seen are activating GNAS gene (OMIM *139320) pathogenic variants, found in about 40% (up to 63% in some series) of growth hormone (GH)-producing adenomas and rarely in other pituitary adenoma types (16, 17, 25). GNAS encodes the gsp oncogene – the stimulatory G-protein subunit alpha (Gsα). The most frequent alterations result in an amino acid substitution of the highly conserved Arg201, and to a lesser extent Gln227, with subsequent constitutive activation of the mutated Gsα subunit, increased adenylate cyclase activity, cAMP production and downstream signaling with abnormal GH transcriptional activation and somatotrope proliferation (26).

GNAS mutation-positive adenomas have been considered to have a favorable clinical profile, including an older age at diagnosis, smaller tumor size, less invasive features and densely granulated microscopic tumor appearance in comparison to their non-mutated counterparts; however, this is not confirmed in all studies (27, 28, 29, 30, 31, 32, 33, 34, 35). With respect to treatment, and particularly GNAS status in relation to somatostatin responsiveness, the literature is inconsistent. Some studies show a favorable effect of GNAS mutational status (29, 34), while others show no effect (25, 28, 33, 35, 36). A recent meta-analysis evaluating GH-suppressive responses after an acute octreotide test showed significantly higher GH reduction in the GNAS mutated pituitary adenomas (17). The influence of GNAS pathogenic variants on the long-term somatostatin analogue (SSA) response is also debatable – a better response by measuring GH is reported by some (30, 37) but no higher percentage of IGF-1 normalization has been shown by others (28, 31, 37). Thus, the presence of a GNAS pathogenic variant is one of the many factors that influence the response to SSA treatment (38).

USP8 mutations

Resistance to the negative glucocorticoid feedback is typical for corticotropinomas. However, somatic pathogenic variants in the nuclear receptor subfamily 3 group C member 1, NR3C1 (OMIM *138040) encoding the glucocorticoid receptor are quite rare (21, 22, 39, 40, 41).

In 2014 next-generation sequencing techniques allowed the identification of recurrent somatic pathogenic variants of the USP8 gene (OMIM *603158) in a significant number of corticotropinomas. USP8 is a deubiquitinase that inhibits lysosomal degradation of the EGF receptor (EGFR). Hotspot pathogenic variants in exon 14 affect the binding motif of the protein that regulates its activity, leading to gain of function. USP8 is cleaved, which enhances its catalytic activity, resulting in subsequently impaired downregulation of EGFR and sustained EGF signaling (20, 21). In USP8-mutated corticotropinomas, enhanced transcription of proopiomelanocortin (POMC) was observed (21, 42). Higher ACTH levels have been demonstrated in USP8-mutated adenomas (20, 43, 44). In another study no absolute difference in ACTH secretion between UPS8 mutated vs non-mutated tumors was noted, but the smaller size of the mutated adenomas suggested that they had relatively high ACTH production capacity (21). USP8 pathogenic variants have not been found in other pituitary tumor types to date (21, 40, 45, 46, 47, 48, 49, 50, 51).

The overall prevalence of USP8 somatic pathogenic variants is 21–62% in corticotropinomas (20, 21, 42, 43, 52, 53, 54). Females predominate over males in some (21, 42, 43, 53) but not other studies (54, 55). In a large cohort of 120 corticotropinomas, smaller tumor size and a lower rate of parasellar expansion was reported in USP8-mutated tumors (21). No such correlation was found in other studies (53, 55). There is inconsistency regarding differences in basal hormonal values between USP8 mutated and wild-type adenomas (20, 21, 42, 43, 44, 52, 53, 55). In pediatric series, female predominance and an older age at diagnosis of USP8 mutated vs wild-type adenomas was noted (52). In regard to treatment, there is high discrepancy in the cure rates after transsphenoidal adenomectomy – higher remission rates in USP8 mutated adenomas in some studies (42, 53), but not in others (21, 43, 55). Higher postoperative free urinary cortisol and ACTH levels were demonstrated in UPS8 mutated patients (43, 44, 52). Up to 5-year recurrence rates were similar with regard to USP8 mutational status (21, 53), although a higher 10-year recurrence rate in USP8 mutated adenomas (58 vs 18%) was reported recently (55). In pediatric series, higher recurrence rates were also observed in USP8 mutated adenomas (52).

With respect to medical treatment, an enhanced effect of pasireotide might occur due to increased transcript levels of SST5R in USP8 mutated adenomas (42). Another potentially useful therapy could be the EGFR inhibitor gefitinib which reduces ACTH secretion in USP8 mutated adenomas in vitro (21).

USP48 and BRAF mutations

A recent study described two other recurrently mutated genes in USP8 wild-type adenomas – BRAF (OMIM *164757) and USP48 (OMIM *716445) in 23 and 16.4% of USP8 wild-type corticotropinomas, respectively (22). There was no clinical difference from wild-type BRAF/USP8 patients, except for the higher midnight ACTH and midnight serum cortisol levels in BRAF V600E-variant-harbouring patients. However, as previous studies failed to identify a role of BRAF pathogenic variants in pituitary tumorigenesis (39, 56, 57), these results need further independent confirmation.

PIK3CA

Phosphatidylinositol 3-kinase is part of the PI3K/Akt signaling pathway which is implicated in the cell survival, proliferation, adhesion, motility and spread (58). It phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate, which is essential for the phosphorylation of AKT (59). Pathogenic variants in hotspots, located on exons 9 and 20 and amplifications of the PIK3CA gene (OMIM *171834) are found in various tumor types and lead to increased PI3K activity, and subsequent phosphorylation and activation of AKT (18, 58).

Frequent genetic alterations in the PIK3CA gene have been found in various types of pituitary adenomas (18, 19). In a Chinese series of 353 pituitary adenomas, 2.3% harbored somatic PIK3CA pathogenic variants. All of the mutated adenomas were invasive and they constituted 8.8% (8/91) of the invasive tumors in that series (one corticotropinoma, two prolactinomas, four non-functioning adenomas and one plurihormonal adenoma). Furthermore, gene amplifications (defined as copy number of PIK3CA ≥ 4) were found in 32.9% (30/91) of invasive and in 26.3% (69/262) of non-invasive pituitary adenomas, with a similar distribution among different tumor types (18). In a Brazilian cohort, PIK3CA gene mutations were present in 12% of adenomas (4/33; non-invasive corticotropinoma and 3 invasive non-functioning adenomas), while genomic amplifications were found in 21.2% (7/33) (19). No pathogenic variants in the PIK3CA gene were found in a cohort of GH-secreting adenomas (45).

As PI3K could be a downstream effector of RAS, screening for RAS pathogenic variants has been performed by Lin et al. (18, 59, 60). HRAS (OMIM *190020) pathogenic variants were found in 6.6% (6/91) of the invasive pituitary adenomas, one of which had a co-existent PIK3CA mutation (18). Individual cases of HRAS pathogenic variants were reported by other groups (61, 62, 63). Regarding the clinical presentation of PIK3CA mutated adenomas, a higher degree of recurrence after surgery has been observed in mutated vs wild-type adenomas: 63 vs 25% respectively (18).

Whole-exome/genome sequencing

After the breakthrough discovery of USP8 pathogenic variants in corticotropinomas, several groups reported results from whole-exome/genome sequencing in other pituitary tumor types, confirming the relatively silent somatic landscape (40, 45, 46, 47, 49, 50, 51). However, in two series of GH-secreting adenomas, despite the absence of recurrent somatic pathogenic variants (except GNAS), abnormalities of several different genes involved in Ca2+ (45, 46) and cAMP signaling (45) were noted. These studies suggest that disruption of calcium signaling could contribute to somatotropinoma formation. On the basis of data from other human tumor types it was speculated that the trigger event could be different in the various tumor types but by targeting the same molecular pathway these could contribute to tumorigenesis (46, 64). A recent study identified variants (in two pituitary adenomas each) in several genes (KIF5A, GRB10, LARS, SP100, TRIP12) whose role remains to be further elucidated (40).

Copy number variations

Frequent copy number variations (CNVs) have also been reported (40, 46, 47, 50). Chromosomal losses are particularly interesting in the context of the two-hit model inactivation of tumor suppressor genes (46). In the absence of subsequent somatic mutation, tumorigenesis might be driven by the coexistence of somatic deletion and epigenetic silencing leading to biallelic inactivation of tumor suppressor genes (46). With respect to the clinical relevance of CNVs, it has been demonstrated that highly genomically disrupted adenomas are more frequently hormonally functional and pathologically atypical, while tumors with rare CNVs are principally non-functional (50). Frequent gains in regions encoding cohesin complex genes have been found, however, without an apparent influence of clinical characteristics of the disrupted adenomas (40). A recent study, focusing on CNVs in pediatric patients with Cushing’s disease, showed that 18.5% (5/27 samples) had a high degree of chromosomal instability (>22% of the genome). The adenomas with widespread genomic aberrations were significantly larger and had higher rates of invasion of the cavernous sinus (65).

A new approach is that of targeting circulating tumor DNA in the plasma. Using a next-generation sequencing approach, Megnis et al. for the first time detected gene variants in circulating free DNA that were also present in the pituitary adenoma tissue of the same patients (66).

Germline mutations in familial and sporadic pituitary adenomas

A limited proportion of pituitary adenomas, approximately 5% arise as part of a heritable or familial syndrome. Such adenomas carry a significant clinical burden as they are usually more aggressive: occur at an early age, have a larger tumor size, show increased invasiveness, and are more likely to demonstrate resistance to standard treatment (67, 68). These features determine the need for efficient screening and early recognition.

Familial isolated pituitary adenomas (FIPA)

Familial pituitary adenomas can be either part of multiple endocrine syndromes or may arise as isolated pituitary adenomas in a familial setting. Over the period 1999–2006 we identified and described familial isolated pituitary adenomas (FIPA) (OMIM #605555) as a novel condition associated with pituitary adenomas (without the presence of other endocrine neoplasia syndromes) in two or more related members of the same kindred (69, 70). FIPA represents around 2% of all pituitary tumors (70). All types of secreting and non-secreting adenomas are described in FIPA, with a predominance of prolactinomas, somatotropinomas, and non-functioning pituitary adenomas. Kindreds can all share the same pituitary adenoma subtype in affected members (homogeneous FIPA) or different pituitary adenoma subtypes can occur within the same family (heterogeneous FIPA) (70). Notably, pituitary adenomas in the setting of FIPA have some clinical characteristics that distinguish them from sporadic adenomas. In FIPA kindreds, prolactinomas, although most prevalent, have lower frequency in comparison with non-FIPA cases – around 38%. It could be partly explained by the higher frequency of somatotropinomas (35%) as compared with the general population of pituitary adenoma patients. FIPA patients usually have earlier disease onset (approximately 4 years) vs non-FIPA cases. In homogenous acromegaly kindreds, the disease onset is early and somatotropinomas are usually large and invasive. Similarly, non-functioning adenomas and prolactinomas in the FIPA setting are larger and more invasive than their non-FIPA counterparts (11, 67, 71).

AIP mutations in FIPA and sporadic pituitary adenomas

In 2006 Vierimaa et al. reported that pathogenic variants of the AIP gene (OMIM *605555) were associated with pituitary tumorigenesis in large kindreds in Finland and elsewhere (10). AIP is a tumor suppressor gene located on chromosome 11q13 (10). The gene encodes a 330-amino acid cytoplasmic protein – the aryl hydrocarbon receptor (AHR)-interacting protein. Different types of pathogenic variants have been described leading to a truncated protein in many cases (11, 71). Besides AHR, AIP has multiple other partners, including chaperones, phosphodiesterases, Gαi proteins, survivin, RET, nuclear receptors, such as thyroid hormone receptor β1, estrogen receptor-α, peroxisome proliferator-activated receptor-α, viral proteins and others (11, 72, 73).

The cAMP-PKA signaling pathway is strongly implicated in pituitary tumorigenesis and the loss of AIP in mutated adenomas has been related to increased cAMP signaling through defective inhibitory Gα protein signaling. Furthermore, the loss of AIP has been associated with reduction in Gαi-2 protein expression in mutated somatotropinomas (74, 75). Loss of this inhibitory G protein signal may be permissive for cellular proliferation and tumor growth. A strongly positive correlation between AIP and Gαi-2 protein expression has also been confirmed in sporadic somatotropinomas (73). The complex interplay between AIP and PKA signaling is further supported by the evidence that AIP interacts physically with both the regulatory (R1α) and the catalytic (Cα) subunits of PKA separately, as well as in complex (76). AIP overexpression led to a decrease in nuclear Cα expression and total PKA activity. Silencing of AIP resulted in PKA pathway activation, and furthermore, the activation was disproportionately elevated under PDE4-specific inhibition, suggesting an additional functional interaction. Of note, the mutant AIP p.R304* interacted to a lesser degree with both PKA subunits (76). Disrupted mutant AIP-PDE4A5 interaction has also been previously reported (77).

Although the role of AHR (the dioxin receptor) in the xenobiotic response has been widely studied, its potential role in the pathogenesis of pituitary adenomas has been recently described (78). Acromegaly was observed with increased incidence in a highly polluted industrial region in Italy (Messina, Sicily) (79). The current prevalence of acromegaly is thought to be 330 cases per million inhabitants and the relative risk of developing the disease was estimated to be eight-fold higher in comparison with a non-polluted area in the same province (79, 80). In a subsequent study it was found that 9/23 (39%) patients from different highly polluted areas in Italy bore a genetic variant of AHR or AIP, as compared with 25.3% (44/187) of patients from non-polluted regions. Notably, genetically variant adenomas in polluted areas had a more severe course of acromegaly, characterized by higher IGF-1 values and larger tumor size and worse response to first-line SSAs in comparison with the other groups (80). It is known that AIP forms a complex with AHR, stabilizing it in the cytoplasm together with a dimer of heat-shock proteins 90 and the co-chaperone p23 and AIP protein expression could influence AHR expression (78, 81, 82). On the other hand, AHR nuclear translocation can be cAMP dependent (83), which is the main signaling pathway disruption in AIP silencing. However, the exact mechanisms of the link between AHR and AIP in terms of tumorigenesis in the pituitary remains to be further elucidated.

Large populations of FIPA kindreds, as well as sporadic adenoma patients have been screened for germline pathogenic variants of AIP. AIP mutation-positive carriers, irrespective of the familial status, have certain distinct clinical characteristics in comparison with their mutation-negative counterparts: predominance of somatotropinomas, younger age at diagnosis (about 24.6 years), larger and more invasive adenomas (11, 84). In the FIPA setting, AIP pathogenic variants are demonstrated in about 20% of families, while in cohorts of unselected apparently sporadic pituitary adenomas AIP pathogenic variants are rarely found – in less than 4% (11, 84). However, in young adults (diagnosed < 30 years of age) with apparently sporadic adenomas (mostly macroadenomas), the prevalence of AIP pathogenic variants was higher, ranging between 1.6 and 13% (85, 86, 87, 88, 89, 90, 91, 92, 93). Further decreasing the age of diagnosis (pediatric/adolescent patients <18 year/old) increases the frequency of AIP pathogenic variants to 11–25% (85, 87, 94, 95, 96, 97, 98). In our large international cohort of giantism patients, the overall frequency of AIP pathogenic variants was 29% (99). Another feature related more commonly to AIP mutated adenomas is pituitary apoplexy (89, 100, 101, 102), especially in pediatric population (89).

Tumoral AIP protein expression may be low in some somatotropinomas even without AIP pathogenic variants and these tumors can have higher invasive rates (103). Decreased AIP protein staining could potentially serve as a marker of invasive potential, along with more traditional markers such as Ki-67 index and p53 positivity (104).

Apart from the unfavorable clinical characteristics, such as young age and macroadenoma at presentation, AIP-mutated adenomas are difficult to treat. In a multicenter collaborative study we demonstrated that although the overall rates of disease control were comparable (70.4 vs 80.5% for AIP mutated somatotropinomas and controls respectively), AIP-mutated somatotropinomas (n = 75) required significantly more neurosurgical interventions than their non-mutated acromegaly counterparts (n = 232) (105).

AIP-mutated somatotropinomas appear to be more resistant to first-generation somatostatin analogues, having significantly lower decreases of GH and IGF-1 and less tumor shrinkage (77, 85, 105, 106, 107). Pretreatment with octreotide increases AIP protein expression (108, 109), while the role of AIP expression level for SSA responsiveness is debatable (68, 103, 104, 108, 109, 110). Overexpression of wild-type AIP increases ZAC1 expression, while AIP knockdown leads to ZAC1 silencing (108); ZAC1 is known to correlate with IGF-1 reduction and tumor shrinkage under octreotide/lanreotide treatment in acromegaly (111, 112). Another causal link was suggested recently through reduced expression of Gαi-2 which mediates somatostatin signaling via the SSTRs (73, 113, 114). Unlike first-generation SSA, similar SSTR5 expression and similar responsiveness to pasireotide irrespective of the AIP expression levels was observed in patients with sporadic acromegaly (107).

Given the well-documented hormonal and tumoral resistance of AIP-mutated somatotropinomas to first-generation SSAs, treatment with a growth hormone receptor antagonist is an alternative option (115). Such adenomas may also be good candidates for pasireotide treatment. Recently, clinical evidence for long-term pasireotide efficacy in first generation SSA-resistant AIP mutated adenomas has been reported (116). Ten-year treatment with pasireotide LAR in one patient led to hormonal control and significant tumor remnant reduction, which allowed discontinuation of the medication with continuous hormonal control (off therapy) for more than two years currently. Similarly, in a second patient hormonal and tumoral control was observed, but this hormonal control was lost after switching to octreotide. AIP protein and SST2 expression was lost, while SST5 staining was positive on immunohistochemistry in that case (116).

Similarly to somatotropinomas, treatment in AIP mutated prolactinomas is also challenging. Only 40% (5/12) were controlled by dopamine agonists in our multicenter study and 4/7 uncontrolled patients required multiple neurosurgeries (105). The explanation behind the lower responsiveness to DA remains to be further elucidated.

Given the aggressive features of AIP mutated adenomas, questions about genetic screening for index cases and relatives are raised. Based on the more prominent characteristics of AIP mutation-positive adenomas, experts’ opinion on the screening referral includes pediatric/adolescent disease onset, pituitary gigantism, FIPA kindreds, macroadenomas (particularly somatotropinomas), occurring ≤30 years of age (117, 118, 119). Some of the FIPA families (8.3–9.5%), negative for AIP pathogenic variants by direct sequencing, could have large genomic deletions, which warrants for the use of multiplex ligation-dependent probe amplification (MLPA) when genetic testing is considered appropriate (98, 100). Recently a clinical risk category system for AIP gene variant screening in pituitary adenomas was proposed, confirming the role of young age at onset (including gigantism), FIPA, macroadenomas and GH excess as independent risk factors. The highest risk (76%) was produced combining homogeneous FIPA somatotropinomas families presenting with a macroadenoma at early age (<18 years) and the risk fell significantly when either of the factors (FIPA, macroadenoma or age >18 years) was absent (120). However, there are little data on the real-life validity of these recommendations. A recent single tertiaryreferral center study reports after results of AIP and MEN1 pathogenic variants/deletions after applying many of the known characteristics of AIP mutated tumors, in addition to novel factors such as SSA resistance in somatotropinomas, or DA resistance in prolactinomas (68). None of the patients had pathogenic variants/deletions in AIP or MEN1 genes. In that series most of the pediatric onset patients had Cushing’s disease, which reinforces the concept that AIP and MEN1 rarely cause pediatric Cushing’s disease. Furthermore, only one patient with gigantism was identified, who did not carry an AIP/MEN1 pathogenic variant. Keeping in mind that the genetic causes are unknown in 50% of gigantism cases, this result is perhaps not very surprising. The results of that recent study suggest that criteria should be carefully interpreted and applied. The age at onset used to trigger screening for AIP-related pituitary adenomas in sporadic patients could be realistically revised downward to well below 30 years at diagnosis and should focus primarily on extensive and/or invasive macroadenomas (68).

Identifying a germline AIP pathogenic variant raises the need to consider familial genetic screening. Pituitary adenomas in AIP pathogenic variant carriers in this setting has low penetrance of about 20–23% (71, 105, 121, 122). Screening is guided by the possibility of diagnosing the disease before manifestation as an invasive macroadenoma, which could bring potential treatment benefits (71, 105). Genetic screening should be particularly targeted at young (pediatric-adolescent) family members who are at higher risk of developing aggressive adenomas. In pathogenic variant carriers, regular clinical observation is warranted (11, 120, 123). The screening could start early in life as a patient as young as 6 years of age with preceding clinical symptoms has been diagnosed with an AIP pathogenic variant and pituitary macroadenoma (124).

X-linked acrogigantism syndrome

X-LAG syndrome (OMIM #300942) was described initially in 2014 when a syndrome of early infant-onset pituitary gigantism was linked to microduplications of chromosome Xq26.3 region, encompassing the GPR101 gene (OMIM *300393) (13, 125). It is a rare condition and less than 40 cases have been identified so far (13, 125, 126, 127, 128, 129, 130, 131). Historically, some of the tallest humans bear clinical features suggestive of X-LAG (132). For example, a recent paleogenetic study found increased copy number of the GPR101 gene in an historic giant (2 m 59 cm) from the early 20th century (133).

In X-LAG the common duplicated region on chromosome Xq26.3 usually encompasses several genes, among which only GPR101 is differentially overexpressed in the affected pituitary adenoma (13). Indeed, in one X-LAG patient a duplication was identified in which only the GPR101 gene was duplicated (127). Duplications are germline in females and somatic in sporadic males with variable level of mosaicism in the latter (126, 127, 130). In three families the germline duplication was transmitted from the affected mother to son and all carriers of the duplication had gigantism (131). The GPR101 gene encodes an orphan G protein-coupled receptor (13, 131). The exact mechanisms of tumorigenesis remain to be fully clarified, but there is evidence that the cAMP-PKA dependent signaling pathway and increased GHRH secretion could be involved (129, 131, 134), in addition to other signaling pathways as indicated by transgenic mouse studies (A Beckers & AF Daly, Personal Communication).

X-LAG syndrome is characterized by some clinical features that discriminate it from other forms of pituitary gigantism. It is a pediatric condition and most of the patients are born with normal height and weight. However, during the first months of their life, as early as 6–12 months, they start to grow excessively and the diagnosis is almost invariably made before the age of 5 years, when their median height standard deviation score (SDS) is about +4–5 SDS, as well as weight +4 SDS. Females prevail over males (2/3 of the cases). Patients have acromegalic features (facial coarsening, including broad nasal bridge, prominent mandible, increased interdental space, and enlarged extremities) and about a third have an increased appetite (125, 126). Most of the patients harbor macroadenomas at diagnosis, generally mixed GH- and PRL-secreting tumors, while a minority have hyperplasia alone. A pattern of multiple microadenomatous foci against a hyperplastic background has also been described. The proliferation index of such adenomas is generally low (Ki-67 LI below 3%) (125, 126, 128) but if the condition is left untreated it eventually ends with aggressive adenoma progression (128). GH and IGF-1 are markedly elevated at diagnosis, with concomitant hyperprolactinemia in more than 80% of the patients. Increased levels of GHRH have been detected in some patients, however not to the extent typical for the ectopic GHRH secretion (13, 125, 129). With respect to treatment, it is complex and a multimodal approach is necessary. Surgery alone can lead to cure but even if GH control is achieved, hypopituitarism remains a life-long burden in many cases. None of the patients responded to first-line somatostatin analogs even at doses typical for adults. The reason for this phenomenon needs to be further clarified as studied tissues from pituitary adenomas of X-LAG patients show preserved SST2 and AIP expression (125). Pegvisomant, alone or in combination, is able to induce IGF-1 normalization (123, 125, 126). Radiotherapy has been applied in a few of patients with unconvincing effects on hormonal hypersecretion (125, 126).

When compared with gigantism in the setting of AIP pathogenic variants or genetically negative cases, X-LAG syndrome could be distinguished by the early childhood or infant onset of disease symptoms, female predominance, presence of acromegalic features at such an early age, increased appetite, marked hormonal hypersecretion, histologically presence of mixed GH-PRL-secreting adenomas and/or hyperplasia; a poor response to SSAs occurs in both AIP mutated and X-LAG-related gigantism (99, 126).

In patients with sporadic acromegaly a missense variant has been observed (p.E308D), affecting the intracellular loop 3 of GPR101. It is relatively rare and its role in pituitary pathogenesis is unknown (13, 126, 135, 136, 137). Other missense variants have been detected in prolactinomas and corticotropinomas with unknown impact on tumorigenesis (137, 138).

Recently the first prenatally diagnosed case of X-LAG was described, offering a unique prospective observation of the natural course of the disease. The mother had a distant history of acrogigantism starting at 4 months of age with complete cure after the resection of the pituitary adenoma at 24 months. She had typical characteristics of X-LAG and the Xq26.3 microduplication was found at preconception testing. The same genetic abnormality was found in her son on a chorionic villus sample, who grew rapidly and had tumor extirpation at the age of 15 months. The immunohistochemical analysis of both adenomas (mother’s and son’s) revealed elevated Ki-67 proliferation index, multiple lineage-specific transcription factors and stem cell markers (139).

Multiple endocrine neoplasia 1 (MEN1)

MEN1(OMIM #131100) is a multiorgan disorder including endocrine and non-endocrine tumors. Clinically it is characterized by the occurrence in a patient of at least two of the three following disorders: hyperparathyroidism, pituitary adenoma, and pancreatic neuroendocrine tumors (NETs). Among the other tumor presentations are facial angiofibroma, collagenomas, lipomas, adrenocortical tumors and carcinoid tumors (140). The MEN1 gene (OMIM *613733) is located on chromosome 11q13 and encodes menin, which is a 610 amino-acid nuclear protein (141, 142). Menin interacts with various proteins involved in transcriptional regulation, genome stability, cell division and proliferation (143). The disorder has autosomal dominant inheritance with high penetrance and in about 10% may arise from de novo pathogenic variants (144). Pituitary adenomas occur in about 15–50% of MEN1 patients (144, 145, 146, 147, 148, 149, 150, 151).

The most prevalent pituitary subtypes are prolactinomas (60–80% of the cases), followed by non-functioning pituitary adenomas (in more recent series – up to 42%), or somatotropinomas (in older series – up to 25%) and corticotropinomas (<5%) (144, 146, 147, 148, 149). In rare cases GH hypersecretion could be caused by ectopic GHRH secretion from NETs (152). A distinctive but uncommon feature of MEN1 pituitary adenomas is the plurihormonal profile (especially prolactin-ACTH and/or GH-positive tumors on immunohistochemistry), as well as the presence of multiple pituitary adenomas (152, 153, 154, 155). In about 15–30% of patients a pituitary adenoma is the first presentation of MEN1 syndrome (140, 147, 148, 149). Among sporadic pituitary adenomas the occurrence of MEN1 is quite rare – less than 3% (152, 156, 157). However, in the pediatric population, similarly to the AIP mutations, the frequency of MEN1 may be higher – up to 6.5% (96, 97) and pituitary adenomas can occur as early as 5 years of age (158). Gigantism due to MEN1 occurs in less than 1% of all pituitary gigantism cases (99). In the setting of MEN1 with pituitary adenomas, females prevail over males (approximately two-thirds of the cohorts), partly due to the higher prevalence of females with prolactinomas (148, 149, 150, 151). Interestingly, when a pituitary adenoma is the first presentation of the syndrome, MEN1 is more frequently diagnosed in males than females (67.3 vs 44.2% ) (149) In series including patients before the introduction of routine screening programs MEN1 pituitary adenomas were predominantly macroadenomas (approximately 80%) and more invasive than their sporadic counterparts (146, 152). A recent nationwide Dutch study of MEN1 pituitary adenomas shows higher frequency of microadenomas – in approximately two-thirds of the cases. Notably, approximately half of the adenomas diagnosed in asymptomatic patients by MRI screening were microadenomas. In the absence of tissue confirmation these could represent incidentalomas, which are commonly seen in the general population and could be a source of bias. In that study pituitary adenomas diagnosed clinically prior to the genetic diagnosis of MEN1 were more frequently macroadenomas versus screening-detected pituitary tumors (81.2 vs 46.3%, P < 0.001) and more often functional (70.2 vs 47.0%, P = 0.009) (148). In the French-Belgium cohort, a poor response to treatment was reported, with normalization of prolactin in only 44% of the patients (146), while in the Dutch series more that 90% of the prolactinomas responded to dopamine agonists (148). According to the last guidelines the treatment approach toward MEN1 pituitary adenomas should be identical to non-MEN1 adenomas (144).

However, moving beyond the MEN1 guidelines, due to the high penetrance of the syndrome, the first presentation with pituitary adenoma in up to a third of the patients, and a higher frequency in young patients with aggressive macroadenomas (96, 144, 146, 159), genetic screening for MEN1 (and AIP), could be considered in patients with young onset, invasive macroadenomas.

MEN4

On genetic testing about 10% of patients with familial and possibly more sporadic MEN1 cases do not harbor MEN1 pathogenic variants (143). MEN4 (OMIM #610755) emerged as a new condition in 2006, when pathogenic variants in the CDKN1B gene (OMIM *600778) were described in a family with a MEN1-like phenotype, including acromegaly, primary hyperparathyroidism and other tumors (12). CDKN1B is located on chromosome 12p13 (160) and encodes p27, a cyclin-dependent kinase inhibitor implicated in the regulation of cell cycle progression and arrest (161, 162). Up to the present day, CDKN1B germline pathogenic variants explain 1.5–3.7% of MEN1 negative patients (163, 164, 165, 166). In the setting of MEN4, pituitary adenomas arose in about 37% of reported cases including somatotropinoma, corticotropinoma, non-functioning pituitary adenoma and prolactinomas, with an age range at onset of 30–79 years (163). In a study of 21 pituitary adenomas (20 corticotropinomas) no somatic CDKN1B alterations were present (167). No germline CDKN1B pathogenic variants have been found in a series of 88 sporadic or familial pediatric pituitary adenomas (97) and in the FIPA setting it was a very rare and questionable finding (168). Genetic screening for this condition should be probably performed only in MEN1 negative kindreds or individuals and routine screening of patients with isolated pituitary adenomas is unlikely to identify CDKN1B mutation carriers.

Carney complex (CNC)

Carney complex (OMIM #160980) is a rare autosomal dominant disease that is characterized by the presence of myxomas, spotty skin pigmentation (lentigines) and endocrine hyperactivity (169, 170). Some of the most common endocrine abnormalities are primary pigmented nodular adrenocortical disease (PPNAD), pituitary adenomas, thyroid nodules, testicular tumors and ovarian cysts. More than 750 cases have been described to date (171) and most cases have PRKAR1A (OMIM *1888830) pathogenic variants (172, 173). Another locus associated with the disease is located on chromosome 2p16 (174) and recently copy number gain at the PRKACB gene locus on chromosome 1p31.1 (OMIM *176892) was described in a patient with abnormal skin pigmentation, myxomas and acromegaly (175). PRKAR1A pathogenic variants lead to loss of function of the protein kinase A 1α regulatory subunit resulting in increased cAMP-dependent PKA activity (171).

In the setting of Carney complex the presentation of pituitary adenomas is generally in the third or fourth decade, and it is usually preceded by other syndromic feature (171). Approximately 75% of the patients have high but asymptomatic levels of GH, IGF-1 and prolactin with abnormal responses to dynamic testing; however, only up to 12% develop overt acromegaly, while prolactinomas are rare (176). CNC contributes less than 1% of gigantism cases (99). In sporadic pituitary adenoma cohorts pathogenic variants of PRKAR1A or in other subunits of PKA do not play frequent role in tumorigenesis (97, 177, 178, 179). In cases with single adenomas surgery could be potentially curative. However, similar to X-LAG, in the setting of CNC, multiple adenomas with surrounding hyperplasia is a known finding (180, 181) and clinical management could require partial or total hypophysectomy (181). Medical treatment with somatostatin analogues or a GH receptor antagonist could also be considered (171).

McCune–Albright syndrome

MAS (OMIM #174800) is a well-established syndromic condition predisposing to acrogigantism and includes the classic triad of precocious puberty (endocrine hyperactivity), fibrous dysplasia and café-au-lait macules (182, 183). It is caused by a post-zygotic, mosaic, gain-of-function mutations in GNAS and the clinical manifestation is determined by the number of affected tissues, and possibly the timing of the mutation’s occurrence (184, 185). In the context of MAS, 10–25% of the patients could have GH hypersecretion leading to gigantism or acromegaly, often accompanied by hyperprolactinemia. MAS accounts for about 5% of gigantism cases (99). Similarly to CNC and X-LAG, pituitary hyperplasia or a distinct pituitary adenoma could be found in the gland (186, 187, 188, 189). Treatment in these patients is challenging due to various factors: difficult surgical access due to bone thickening, presence of diffuse pituitary hyperplasia, partial response to somatostatin analogues, and the risk of sarcoma transformation of affected bone, following radiotherapy. Treatment with pegvisomant could be useful in such cases (123, 187, 188, 189, 190, 191).

Pheochromocytoma/paraganglioma and pituitary adenomas association (3PAs)

The coexistence of these tumors, termed 3PAs (15), is quite rare, although it had been described historically (192). The interrelation between the tumors has been strengthened recently by the finding of a germline SDHD (OMIM *602690) pathogenic variant in a patient with pheochromocytoma, paragangliomas and acromegaly, strengthening a pathogenetic role of the mutation by loss of heterozygosity for SDHD and downregulation of the corresponding protein in the pituitary adenoma tissue (14). Approximately 80 cases with this association have been described in literature and genetic studies in recent cases revealed genetic defects in approximately one-third of cases (193, 194, 195, 196, 197, 198). Most of the patients had mutations in one of the four genes encoding SDH subunits that are previously known to predispose to pheochromocytoma/paraganglioma (193).

The succinate dehydrogenase complex forms the mitochondrial complex II on the inner mitochondrial membrane and consists of four subunits (A, B, C and D) and an associated assembly factor (SDHAF2). It is responsible for electron transfer in the respiratory chain and converts succinate to fumarate (199). An impaired SDH complex mimics hypoxia, and oncogenesis is likely to be mediated by hypoxia-inducible factor-1 α (HIF-1α)-related pathways (200).

Clinically, the potentially SDHx-mutated pituitary adenomas can be prolactinomas, somatotropinomas or non-functional adenomas. Most are macroadenomas with an aggressive clinical course – requiring surgery and with poor response to somatostatin analogues (193). One carcinoma has been described (196). A distinctive pathologic feature of SDHx-mutated pituitary adenomas is an extensive vacuolization of the cytoplasm (201).

Recently, the 3PA syndrome was associated with germline MYC-associated factor X (MAX) (OMIM *154950) pathogenic variants or intragenic deletions in five patients (three prolactinomas and two somatotropinomas) (194, 195, 202). Single cases of 3PAs have also been described in the setting of MEN1, MEN2 or von Hippel–Lindau disease (193) Screening for SDHx mutations in the pool of sporadic pituitary adenomas without personal or familial syndromic history is not warranted as they are quite rare (15, 201, 203, 204). Of note intragenic deletions such as those seen in MAX require MLPA analysis as they are not detectable on Sanger sequencing (195).

Other germline conditions

Growth hormone excess causing acromegaly or gigantism can rarely be part of neurofibromatosis type 1 (NF1) (OMIM #162200), characterized by neurofibromas, café-au-lait macules, intertriginous freckling, osseous lesions, Lisch nodules and optic pathway gliomas (205, 206). GH hypersecretion with an increase in growth velocity has been observed in about 10% of children with optic pathway gliomas, which is more frequent than previously thought (207). In accordance with other data in the literature affected children have an optic chiasm tumor but not a pituitary adenoma (207). In such cases the pathogenesis of GH excess has been considered to be either due to loss of somatostatinergic inhibition or presence of overactive GHRH secretion in the optic pathway tumor (207, 208). In a series of ten patients with overgrowth and NF1 in the National Institute of Health, including children and adults, a link between pituitary tumorigenesis, NF1 and GH excess has been confirmed. Of note, similarly to MAS and CNC, pituitary hyperplasia has been described in some cases. Given the probability of increased oncological risk, or worsening neurofibromas, pain, or endocrinopathies, it is strongly advisable to investigate NF1 patients for GH excess, including appropriate sellar region and optic tract imaging (208).

Pituitary blastomas (pituitary tumor with embryonic origin) are very rare and can arise in the setting of DICER1 syndrome (OMIM #601200), known also as pleuropulmonary blastoma-familial tumor. DICER1 (OMIM *606241) encodes a protein responsible for miRNA maturation. Clinically it presents in early infancy with Cushing’s syndrome with high mortality (9, 209, 210, 211).

Recently, another potential pituitary adenoma predisposition gene has been described – CABLES1 (CDK5 and ABL1 enzyme substrate 1) (OMIM *609194) (212). CABLES1 protein is implicated in negative cell cycle regulation in corticotropes in response to glucocorticoids. Usually the physiologic adrenal-pituitary negative feedback is disrupted in corticotropinomas and CABLES1 protein expression is often lost (213). Given this background, germline and/or tumor DNA samples from an international cohort of 146 pediatric and 35 adult patients was studied for CABLES1 gene variants or copy number variations (212). Four heterozygous missense variants were found in two pediatric and two young adult Cushing’s disease patients. Functionally these variants appeared to interfere with the normal inhibition of cell growth by CABLES1 in vitro. The possible tumorigenic mechanism could be linked to increased CDKN1B degradation as all mutated samples showed markedly reduced nuclear CDKN1B staining and preserved, although weaker, CABLES1 immunohistochemical expression. Clinically, all four corticotropinomas were macroadenomas with high Ki-67 index, three of them had extrasellar extension and three required second transsphenoidal surgery (212). Isolated cases of corticotropinomas in the setting of congenital adrenal hyperplasia (OMIM #201910) with pathogenic variants in the 21-hydroxylase enzyme gene (CYP21A2) (OMIM *613815) and in the setting of X-linked congenital adrenal hypoplasia (OMIM #300200) with pathogenic variant in the NR0B1 (nuclear receptor subfamily 0 group B member 1) (OMIM *300473) gene have been reported (214, 215, 216).

Discussion and conclusions

Scientific progress has led to the discovery of numerous new genetic and genomic disruptions in patients with pituitary tumors. The most frequent genetic causes are summarized in Table 1. While for somatic pathogenic variants discriminative clinical features can be quite subtle, most germline pathogenic variants, though rare, present with particular clinical features. To help prompt diagnosis and treatment, integrated screening could be offered for germline variants (Fig. 1). Pediatric patients (up to 18 years) with isolated pituitary adenomas and young adults (<30 years) with isolated aggressive or large pituitary macroadenomas should be screened for AIP and MEN1 gene variants or deletions. Very early-onset cases of somatotropinomas in children that are suggestive for XLAG should be screened for GPR101 duplications via array comparative genome hybridization, and droplet digital PCR can be used for confirmatory purposes. Patients with FIPA should undergo genetic screening for AIP variants/deletions (AIP-negative FIPA families with gigantism cases should be considered for X-LAG screening). Patients or kindreds with MEN1 phenotype without MEN1 pathogenic variants could be screened for CDKN1B gene variants; CDKN1B pathogenic variants rarely lead to isolated pituitary adenomas. Genetic screening for Carney complex tends to be guided more by the presence of typical syndromic features rather than any specific characteristics of the pituitary adenomas that occur in Carney complex. The combination of pheochromocytoma and/or paraganglioma and pituitary adenoma could be indicative of SDHx or MAX genetic alterations, including pathogenic variants and deletions. As the availability of multi-gene panels is increasing, a more straightforward approach is to use multigene panels in next-generation sequencing platforms: GNAS, PRKAR1A, MEN1, CDKN1B, SDHx, MAX in patients with concomitant extra-pituitary pathology, and AIP, MEN1 and GPR101 in patients with a familial history of pituitary adenomas or young patients with aggressive adenomas. The relatives of index cases could be offered genetic counseling or screening, or close clinical and radiological surveillance according to the genetic disruption. Prospectively diagnosed mutation carriers are managed according to the current guidelines or clinical recommendations for each condition, where they exist.

Figure 1
Figure 1

Screening for genetic causes of pituitary adenomas. AIP, aryl hydrocarbon receptor-interacting protein gene; CDKN1B, cyclin-dependent kinase inhibitor 1B; CNC, Carney complex; FIPA, familial isolated pituitary adenoma; GNAS, guanine nucleotide (GTP)-binding protein alpha stimulating; GPR101, G protein-coupled receptor 101 gene; MAS, McCune Albright syndrome; MAX, MYC-associated factor X; MEN1, multiple endocrine neoplasia type 1 gene; MEN4, multiple endocrine neoplasia type 4; PA/PGL/PHEO, pituitary adenoma/paraganlioma/pheochromocytoma; PHPT, primary hyperparathyroidism; PRKACB, Protein Kinase cAMP-Activated Catalytic Subunit Beta; PRKAR1A, protein kinase type I-alpha regulatory subunit gene; SDHAF2, succinate dehydrogenase assembly factor 2 gene; SHDx, succinate dehydrogenase complex genes; X-LAG, X-linked acrogigantism. The figure is adapted by the authors from Rostomyan L and Beckers A. Screening for genetic causes of growth hormone hypersecretion. Growth Hormone and IGF Research 2016 30–31 52–57 with permission.

Citation: European Journal of Endocrinology 181, 6; 10.1530/EJE-19-0602

Table 1

Overview of somatic and germline genetic causes of pituitary adenomas.
Level of disruption Gene Clinical condition Clinical characteristics Treatment characteristics
Somatic GNAS 30–60% of somatotropinomas May be smaller, less invasive, densely granulated, arising at an older age Better GH response to acute octreotide test

Inconsistency on long-term results
MAS (post-zygotic mosaic mutations) Café-au lait macules, fibrous dysplasia, endocrine hyperactivity 10–15% have acromegaly and/or gigantism

Pituitary hyperplasia		 Difficult surgical approach

Resistance to SSA

Response to PEG

Radiotherapy complications
PIKA3CA All pituitary types Predominantly invasive adenomas Higher recurrence rates after surgery
USP8 30-60% of corticotropinomas Female predominance

Inconsistency in regards to other clinical characteristics		 Inconsistency in regards to cure and recurrence rates

In vitro response to gefitinib
USP48 ~20% of USP8 wild-type corticotropinomas No difference with wild-type adenomas No difference with wild-type adenomas
BRAF ~16% of USP8 wild-type corticotropinomas Higher midnight ACTH and cortisol In vitro response to vemurafenib
Germline AIP ~20% of PA in FIPA

~up to 13% of young sporadic macroadenomas ~up to 23% of pediatric pituitary adenomas ~29% of pituitary gigantism		 Younger age at diagnosis (<30 years)

Male predominance in somatotropinomas

Large invasive adenomas		 Higher rates of repeated surgery

Resistance to 1st generation SSAs

Response to PEG

Resistance to DA in prolactinomas
GPR101 (mosaicism in sporadic male patients) X-LAG syndrome

10% of gigantism		 Early childhood onset (<12–36 months of age)

Acromegalic features

Increased appetite

Concomitant hyperprolactinemia

Hyperplasia

GHRH elevation		 Need of multimodal treatment

Unsuccessful surgery in many cases

Resistance to SSA

Response to PEG
MEN1 Up to 50% of MEN1 have a PA (PHPT, PA, pancreatic and other tumors) Mainly prolactinomas

Plurihormonal and multiple adenomas

Female predominance

Larger and more invasive in some series		 Resistance to DA in some series and need of surgery for prolactinomas
CDKN1B ~37% of MEN4 have a PA Somatotropinoma, corticotropinoma, NFPA, prolactinoma
PRKAR1A CNC (skin pigmentations, myxomas, endocrine hyperactivity) Up to 12% overt acromegaly Partial or total hypophysectomy in cases with multiple adenomas and hyperplasia
PRKACB Multiple adenomas with surrounding hyperplasia
SDHx, SDHA, SDHB, SDHC, SDHD, SDHAF2 ~30% of PA in 3PAs (pheochromocytoma and/or paraganglioma and PA) Prolactinoma, somatotropinoma, NFPA

Extensive vacuolization of the cytoplasm

Mostly macroadenomas with aggressive clinical course		 Multimodal approach
MAX 3PAs

Aggressive pheochromocytoma		 5 cases (3 prolactinomas, 2 somatotropinomas)
NF1 Neurofibromatosis type 1 Acromegaly or gigantism (increased growth velocity in 10% of children with optic pathway gliomas) Single cases
DICER1 DICER1 syndrome (pleuropulmonary blastoma- familial tumor) Cushing’s disease with high mortality in early infancy Single cases
CABLES1 Ccorticotropinomas Macroadenomas with high Ki-67 index and extrasellar extention Repeated surgery

ACTH, adrenocorticotropic hormone; AIP, aryl hydrocarbon receptor-interacting protein; CABLES1, CDK5 and ABL1 enzyme substrate 1; CDKN1B, cyclin-dependent kinase inhibitor 1B; CNC, Carney complex; DA, dopamine agonist; FIPA, familial isolated pituitary adenoma; GH, growth hormone; GNAS, guanine nucleotide (GTP)-binding protein alpha stimulating; GPR101, G protein-coupled receptor 101 gene; MAS, McCune Albright syndrome; MAX, MYC-associated factor X; MEN1, multiple endocrine neoplasia type 1 gene; MEN4, multiple endocrine neoplasia type 4; NF1 , neurofibromatosis type 1; NFPA, non-functional pituitary adenoma; PA, pituitary adenoma; PEG, Pegvisomant; PHPT, primary hyperparathyroidism; PIKA3CA, phosphatidylinositol 3 kinase alpha subunit; PRKACB, protein kinase CAMP-activated catalytic subunit beta; PRKAR1A, protein kinase type I-alpha regulatory subunit gene; SDHAF2, succinate dehydrogenase assembly factor 2 gene; SHDx, succinate dehydrogenase complex genes; SSA, somatostatin analogs; USP48, ubiquitin-specific protease 48; USP8, ubiquitin-specific protease 8; X-LAG, X-linked acrogigantism.

Apart from clarifying their pathogenesis, new genetic findings provide insight into the clinical characteristics and behaviors of mutated adenoma patients that could discriminate them from the overall population of pituitary adenoma patients and possibly serve as a basis for targeted molecular and individualized treatment approach. Overall the genetic causes of sporadic and hereditary pituitary adenomas are unknown in most cases, which argues for collaborative research studies to identify novel molecular genetic mechanisms.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

The work was supported by grants (to AB) from the JABBS Foundation, UK, the Fonds d’Investissement Pour la Recherche Scientifique of the CHU de Liège and the Bulgarian Ministry of Education and Science under the National Program for Research "Young Scientist and Postdoctoral Students".

References

  • 1↑

    Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, McCutcheon IE. The prevalence of pituitary adenomas: a systematic review. Cancer 2004 613–619. (https://doi.org/10.1002/cncr.20412)

    • Search Google Scholar
    • Export Citation
  • 2↑

    Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A. High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. Journal of Clinical Endocrinology and Metabolism 2006 4769–4775. (https://doi.org/10.1210/jc.2006-1668)

    • Search Google Scholar
    • Export Citation
  • 3↑

    Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S. Clonal origin of pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 1990 1427–1433. (https://doi.org/10.1210/jcem-71-6-1427)

    • Search Google Scholar
    • Export Citation
  • 4↑

    Clayton RN, Farrell WE. Clonality of pituitary tumours: more complicated than initially envisaged? Brain Pathology 2001 313–327. (https://doi.org/10.1111/j.1750-3639.2001.tb00402.x)

    • Search Google Scholar
    • Export Citation
  • 5↑

    Vandeva S, Jaffrain-Rea ML, Daly AF, Tichomirowa M, Zacharieva S, Beckers A. The genetics of pituitary adenomas. Best Practice and Research: Clinical Endocrinology and Metabolism 2010 461–476. (https://doi.org/10.1016/j.beem.2010.03.001)

    • Search Google Scholar
    • Export Citation
  • 6↑

    Xekouki P, Azevedo M, Stratakis CA. Anterior pituitary adenomas: inherited syndromes, novel genes and molecular pathways. Expert Review of Endocrinology and Metabolism 2010 697–709. (https://doi.org/10.1586/eem.10.47)

    • Search Google Scholar
    • Export Citation
  • 7↑

    Zhang T, Yang Z, Gao H. Advancements in the study of miRNA regulation during the cell cycle in human pituitary adenomas. Journal of Neuro-Oncology 2017 253–258. (https://doi.org/10.1007/s11060-017-2518-5)

    • Search Google Scholar
    • Export Citation
  • 8↑

    Zhou Y, Zhang X, Klibanski A. Genetic and epigenetic mutations of tumor suppressive genes in sporadic pituitary adenoma. Molecular and Cellular Endocrinology 2014 16–33. (https://doi.org/10.1016/j.mce.2013.09.006)

    • Search Google Scholar
    • Export Citation
  • 9↑

    Marques P, Korbonits M. Genetic aspects of pituitary adenomas. Endocrinology and Metabolism Clinics of North America 2017 335–374. (https://doi.org/10.1016/j.ecl.2017.01.004)

    • Search Google Scholar
    • Export Citation
  • 10↑

    Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, Tuppurainen K, Ebeling TM, Salmela PI & Paschke R et al.Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 2006 1228–1230. (https://doi.org/10.1126/science.1126100)

    • Search Google Scholar
    • Export Citation
  • 11↑

    Beckers A, Aaltonen LA, Daly AF, Karhu A. Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocrine Reviews 2013 239–277. (https://doi.org/10.1210/er.2012-1013)

    • Search Google Scholar
    • Export Citation
  • 12↑

    Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, Fend F, Graw J, Atkinson MJ. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. PNAS 2006 15558–15563. (https://doi.org/10.1073/pnas.0603877103)

    • Search Google Scholar
    • Export Citation
  • 13↑

    Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF & Caberg JH et al.Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. New England Journal of Medicine 2014 2363–2374. (https://doi.org/10.1056/NEJMoa1408028)

    • Search Google Scholar
    • Export Citation
  • 14↑

    Xekouki P, Pacak K, Almeida M, Wassif CA, Rustin P, Nesterova M, de la Luz Sierra M, Matro J, Ball E & Azevedo M et al.Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: a new association for SDH? Journal of Clinical Endocrinology and Metabolism 2012 E357–E366. (https://doi.org/10.1210/jc.2011-1179)

    • Search Google Scholar
    • Export Citation
  • 15↑

    Xekouki P, Szarek E, Bullova P, Giubellino A, Quezado M, Mastroyannis SA, Mastorakos P, Wassif CA, Raygada M & Rentia N et al.Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. Journal of Clinical Endocrinology and Metabolism 2015 E710–E719. (https://doi.org/10.1210/jc.2014-4297)

    • Search Google Scholar
    • Export Citation
  • 16↑

    Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 1989 692–696. (https://doi.org/10.1038/340692a0)

    • Search Google Scholar
    • Export Citation
  • 17↑

    Efstathiadou ZA, Bargiota A, Chrisoulidou A, Kanakis G, Papanastasiou L, Theodoropoulou A, Tigas SK, Vassiliadi DA, Alevizaki M, Tsagarakis S. Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis. Pituitary 2015 861–867. (https://doi.org/10.1007/s11102-015-0662-5)

    • Search Google Scholar
    • Export Citation
  • 18↑

    Lin Y, Jiang X, Shen Y, Li M, Ma H, Xing M, Lu Y. Frequent mutations and amplifications of the PIK3CA gene in pituitary tumors. Endocrine-Related Cancer 2009 301–310. (https://doi.org/10.1677/ERC-08-0167)

    • Search Google Scholar
    • Export Citation
  • 19↑

    Murat CB, Braga PB, Fortes MA, Bronstein MD, Correa-Giannella ML, Giorgi RR. Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas. Brazilian Journal of Medical and Biological Research 2012 851–855. (https://doi.org/10.1590/s0100-879x2012007500115)

    • Search Google Scholar
    • Export Citation
  • 20↑

    Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K & Saeki Y et al.Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nature Genetics 2015 31–38. (https://doi.org/10.1038/ng.3166)

    • Search Google Scholar
    • Export Citation
  • 21↑

    Ma ZY, Song ZJ, Chen JH, Wang YF, Li SQ, Zhou LF, Mao Y, Li YM, Hu RG & Zhang ZY et al.Recurrent gain-of-function USP8 mutations in Cushing’s disease. Cell Research 2015 306–317. (https://doi.org/10.1038/cr.2015.20)

    • Search Google Scholar
    • Export Citation
  • 22↑

    Chen J, Jian X, Deng S, Ma Z, Shou X, Shen Y, Zhang Q, Song Z, Li Z & Peng H et al.Identification of recurrent USP48 and BRAF mutations in Cushing’s disease. Nature Communications 2018 3171. (https://doi.org/10.1038/s41467-018-05275-5)

    • Search Google Scholar
    • Export Citation
  • 23↑

    Bertherat J, Chanson P, Montminy M. The cyclic adenosine 3′,5′-monophosphate-responsive factor CREB is constitutively activated in human somatotroph adenomas. Molecular Endocrinology 1995 777–783. (https://doi.org/10.1210/mend.9.7.7476961)

    • Search Google Scholar
    • Export Citation
  • 24↑

    Sands WA, Palmer TM. Regulating gene transcription in response to cyclic AMP elevation. Cellular Signalling 2008 460–466. (https://doi.org/10.1016/j.cellsig.2007.10.005)

    • Search Google Scholar
    • Export Citation
  • 25↑

    Park C, Yang I, Woo J, Kim S, Kim J, Kim Y, Sohn S, Kim E, Lee M & Park H et al.Somatostatin (SRIF) receptor subtype 2 and 5 gene expression in growth hormone-secreting pituitary adenomas: the relationship with endogenous srif activity and response to octreotide. Endocrine Journal 2004 227–236. (https://doi.org/10.1507/endocrj.51.227)

    • Search Google Scholar
    • Export Citation
  • 26↑

    Levine MA. Clinical implications of genetic defects in G proteins: oncogenic mutations in G alpha s as the molecular basis for the McCune-Albright syndrome. Archives of Medical Research 1999 522–531. (https://doi.org/10.1016/S0188-4409(99)00075-2)

    • Search Google Scholar
    • Export Citation
  • 27↑

    Landis CA, Harsh G, Lyons J, Davis RL, McCormick F, Bourne HR. Clinical characteristics of acromegalic patients whose pituitary tumors contain mutant Gs protein. Journal of Clinical Endocrinology and Metabolism 1990 1416–1420. (https://doi.org/10.1210/jcem-71-6-1416)

    • Search Google Scholar
    • Export Citation
  • 28↑

    Freda PU, Chung WK, Matsuoka N, Walsh JE, Kanibir MN, Kleinman G, Wang Y, Bruce JN, Post KD. Analysis of GNAS mutations in 60 growth hormone secreting pituitary tumors: correlation with clinical and pathological characteristics and surgical outcome based on highly sensitive GH and IGF-I criteria for remission. Pituitary 2007 275–282. (https://doi.org/10.1007/s11102-007-0058-2)

    • Search Google Scholar
    • Export Citation
  • 29↑

    Yang I, Park S, Ryu M, Woo J, Kim S, Kim J, Kim Y, Choi Y. Characteristics of gsp-positive growth hormone-secreting pituitary tumors in Korean acromegalic patients. European Journal of Endocrinology 1996 720–726. (https://doi.org/10.1530/eje.0.1340720)

    • Search Google Scholar
    • Export Citation
  • 30↑

    Barlier A, Gunz G, Zamora AJ, Morange-Ramos I, Figarella-Branger D, Dufour H, Enjalbert A, Jaquet P. Pronostic and therapeutic consequences of Gs alpha mutations in somatotroph adenomas. Journal of Clinical Endocrinology and Metabolism 1998 1604–1610. (https://doi.org/10.1210/jcem.83.5.4797)

    • Search Google Scholar
    • Export Citation
  • 31↑

    Fougner SL, Casar-Borota O, Heck A, Berg JP, Bollerslev J. Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clinical Endocrinology 2012 96–102. (https://doi.org/10.1111/j.1365-2265.2011.04163.x)

    • Search Google Scholar
    • Export Citation
  • 32↑

    Larkin S, Reddy R, Karavitaki N, Cudlip S, Wass J, Ansorge O. Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas. European Journal of Endocrinology 2013 491–499. (https://doi.org/10.1530/EJE-12-0864)

    • Search Google Scholar
    • Export Citation
  • 33↑

    Kim HJ, Kim MS, Park YJ, Kim SW, Park DJ, Park KS, Kim SY, Cho BY, Lee HK & Jung HW et al.Prevalence of Gs alpha mutations in Korean patients with pituitary adenomas. Journal of Endocrinology 2001 221–226. (https://doi.org/10.1677/joe.0.1680221)

    • Search Google Scholar
    • Export Citation
  • 34↑

    Spada A, Arosio M, Bochicchio D, Bazzoni N, Vallar L, Bassetti M, Faglia G. Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase. Journal of Clinical Endocrinology and Metabolism 1990 1421–1426. (https://doi.org/10.1210/jcem-71-6-1421)

    • Search Google Scholar
    • Export Citation
  • 35↑

    Yasufuku-Takano J, Takano K, Morita K, Takakura K, Teramoto A, Fujita T. Does the prevalence of gsp mutations in GH-secreting pituitary adenomas differ geographically or racially? Prevalence of gsp mutations in Japanese patients revisited. Clinical Endocrinology 2006 91–96. (https://doi.org/10.1111/j.1365-2265.2005.02423.x)

    • Search Google Scholar
    • Export Citation
  • 36↑

    Fougner SL, Borota OC, Berg JP, Hald JK, Ramm-Pettersen J, Bollerslev J. The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma. Clinical Endocrinology 2008 458–465. (https://doi.org/10.1111/j.1365-2265.2007.03065.x)

    • Search Google Scholar
    • Export Citation
  • 37↑

    Mendoza V, Sosa E, Espinosa-de-Los-Monteros AL, Salcedo M, Guinto G, Cheng S, Sandoval C, Mercado M. GSPalpha mutations in Mexican patients with acromegaly: potential impact on long term prognosis. Growth Hormone and IGF Research 2005 28–32. (https://doi.org/10.1016/j.ghir.2004.10.001)

    • Search Google Scholar
    • Export Citation
  • 38↑

    Puig Domingo M. Treatment of acromegaly in the era of personalized and predictive medicine. Clinical Endocrinology 2015 3–14. (https://doi.org/10.1111/cen.12731)

    • Search Google Scholar
    • Export Citation
  • 39↑

    Albani A, Perez-Rivas LG, Reincke M, Theodoropoulou M. Pathogenesis of Cushing disease: an update on the genetics of corticotropinomas. Endocrine Practice 2018 907–914. (https://doi.org/10.4158/EP-2018-0111)

    • Search Google Scholar
    • Export Citation
  • 40↑

    Song ZJ, Reitman ZJ, Ma ZY, Chen JH, Zhang QL, Shou XF, Huang CX, Wang YF, Li SQ & Mao Y et al.The genome-wide mutational landscape of pituitary adenomas. Cell Research 2016 1255–1259. (https://doi.org/10.1038/cr.2016.114)

    • Search Google Scholar
    • Export Citation
  • 41↑

    Dahia PL, Honegger J, Reincke M, Jacobs RA, Mirtella A, Fahlbusch R, Besser GM, Chew SL, Grossman AB. Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors. Journal of Clinical Endocrinology and Metabolism 1997 1088–1093. (https://doi.org/10.1210/jcem.82.4.3861)

    • Search Google Scholar
    • Export Citation
  • 42↑

    Hayashi K, Inoshita N, Kawaguchi K, Ibrahim Ardisasmita A, Suzuki H, Fukuhara N, Okada M, Nishioka H, Takeuchi Y & Komada M et al.The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing’s disease. European Journal of Endocrinology 2016 213–226. (https://doi.org/10.1530/EJE-15-0689)

    • Search Google Scholar
    • Export Citation
  • 43↑

    Perez-Rivas LG, Theodoropoulou M, Ferrau F, Nusser C, Kawaguchi K, Stratakis CA, Faucz FR, Wildemberg LE, Assie G & Beschorner R et al.The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushing’s disease. Journal of Clinical Endocrinology and Metabolism 2015 E997–1004. (https://doi.org/10.1210/jc.2015-1453)

    • Search Google Scholar
    • Export Citation
  • 44↑

    Perez-Rivas LG, Theodoropoulou M, Puar TH, Fazel J, Stieg MR, Ferrau F, Assie G, Gadelha MR, Deutschbein T & Fragoso MC et al.Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson’s tumor. European Journal of Endocrinology 2018 57–63. (https://doi.org/10.1530/EJE-17-0634)

    • Search Google Scholar
    • Export Citation
  • 45↑

    Ronchi CL, Peverelli E, Herterich S, Weigand I, Mantovani G, Schwarzmayr T, Sbiera S, Allolio B, Honegger J & Appenzeller S et al.Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas. European Journal of Endocrinology 2016 363–372. (https://doi.org/10.1530/EJE-15-1064)

    • Search Google Scholar
    • Export Citation
  • 46↑

    Valimaki N, Demir H, Pitkanen E, Kaasinen E, Karppinen A, Kivipelto L, Schalin-Jantti C, Aaltonen LA, Karhu A. Whole-genome sequencing of growth hormone (GH)-secreting pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 2015 3918–3927. (https://doi.org/10.1210/jc.2015-3129)

    • Search Google Scholar
    • Export Citation
  • 47↑

    Hage M, Viengchareun S, Brunet E, Villa C, Pineau D, Bouligand J, Teglas JP, Adam C, Parker F & Lombes M et al.Genomic alterations and complex subclonal architecture in sporadic GH-secreting pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 2018 1929–1939. (https://doi.org/10.1210/jc.2017-02287)

    • Search Google Scholar
    • Export Citation
  • 48↑

    Newey PJ, Nesbit MA, Rimmer AJ, Head RA, Gorvin CM, Attar M, Gregory L, Wass JA, Buck D & Karavitaki N et al.Whole-exome sequencing studies of nonfunctioning pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 2013 E796–E800. (https://doi.org/10.1210/jc.2012-4028)

    • Search Google Scholar
    • Export Citation
  • 49↑

    Lan X, Gao H, Wang F, Feng J, Bai J, Zhao P, Cao L, Gui S, Gong L, Zhang Y. Whole-exome sequencing identifies variants in invasive pituitary adenomas. Oncology Letters 2016 2319–2328. (https://doi.org/10.3892/ol.2016.5029)

    • Search Google Scholar
    • Export Citation
  • 50↑

    Bi WL, Horowitz P, Greenwald NF, Abedalthagafi M, Agarwalla PK, Gibson WJ, Mei Y, Schumacher SE, Ben-David U & Chevalier A et al.Landscape of genomic alterations in pituitary adenomas. Clinical Cancer Research 2017 1841–1851. (https://doi.org/10.1158/1078-0432.CCR-16-0790)

    • Search Google Scholar
    • Export Citation
  • 51↑

    Sapkota S, Horiguchi K, Tosaka M, Yamada S, Yamada M. Whole-exome sequencing study of thyrotropin-secreting pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 2017 566–575. (https://doi.org/10.1210/jc.2016-2261)

    • Search Google Scholar
    • Export Citation
  • 52↑

    Faucz FR, Tirosh A, Tatsi C, Berthon A, Hernandez-Ramirez LC, Settas N, Angelousi A, Correa R, Papadakis GZ & Chittiboina P et al.Somatic USP8 gene mutations are a common cause of pediatric Cushing disease. Journal of Clinical Endocrinology and Metabolism 2017 2836–2843. (https://doi.org/10.1210/jc.2017-00161)

    • Search Google Scholar
    • Export Citation
  • 53↑

    Losa M, Mortini P, Pagnano A, Detomas M, Cassarino MF, Pecori Giraldi F. Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas. Endocrine 2019 240–246. (https://doi.org/10.1007/s12020-018-1776-0)

    • Search Google Scholar
    • Export Citation
  • 54↑

    Ballmann C, Thiel A, Korah HE, Reis AC, Saeger W, Stepanow S, Kohrer K, Reifenberger G, Knobbe-Thomsen CB & Knappe UJ et al.USP8 mutations in pituitary Cushing adenomas-targeted analysis by next-generation sequencing. Journal of the Endocrine Society 2018 266–278. (https://doi.org/10.1210/js.2017-00364)

    • Search Google Scholar
    • Export Citation
  • 55↑

    Albani A, Perez-Rivas LG, Dimopoulou C, Zopp S, Colon-Bolea P, Roeber S, Honegger J, Flitsch J, Rachinger W & Buchfelder M et al.The USP8 mutational status may predict long-term remission in patients with Cushing’s disease. Clinical Endocrinology 2018 89454–458. (https://doi.org/10.1111/cen.13802)

    • Search Google Scholar
    • Export Citation
  • 56↑

    De Martino I, Fedele M, Palmieri D, Visone R, Cappabianca P, Wierinckx A, Trouillas J, Fusco A. B-RAF mutations are a rare event in pituitary adenomas. Journal of Endocrinological Investigation 2007 RC1–RC3. (https://doi.org/10.1007/BF03347386)

    • Search Google Scholar
    • Export Citation
  • 57↑

    Ewing I, Pedder-Smith S, Franchi G, Ruscica M, Emery M, Vax V, Garcia E, Czirjak S, Hanzely Z & Kola B et al.A mutation and expression analysis of the oncogene BRAF in pituitary adenomas. Clinical Endocrinology 2007 348–352. (https://doi.org/10.1111/j.1365-2265.2006.02735.x)

    • Search Google Scholar
    • Export Citation
  • 58↑

    Samuels Y, Ericson K. Oncogenic PI3K and its role in cancer. Current Opinion in Oncology 2006 77–82. (https://doi.org/10.1097/01.cco.0000198021.99347.b9)

    • Search Google Scholar
    • Export Citation
  • 59↑

    Karakas B, Bachman KE, Park BH. Mutation of the PIK3CA oncogene in human cancers. British Journal of Cancer 2006 455–459. (https://doi.org/10.1038/sj.bjc.6602970)

    • Search Google Scholar
    • Export Citation
  • 60↑

    Suhardja A, Kovacs K, Rutka J. Genetic basis of pituitary adenoma invasiveness: a review. Journal of Neuro-Oncology 2001 195–204. (https://doi.org/10.1023/a:1010655419332)

    • Search Google Scholar
    • Export Citation
  • 61↑

    Karga HJ, Alexander JM, Hedley-Whyte ET, Klibanski A, Jameson JL. Ras mutations in human pituitary tumors. Journal of Clinical Endocrinology and Metabolism 1992 914–919. (https://doi.org/10.1210/jcem.74.4.1312542)

    • Search Google Scholar
    • Export Citation
  • 62↑

    Pei L, Melmed S, Scheithauer B, Kovacs K, Prager D. H-ras mutations in human pituitary carcinoma metastases. Journal of Clinical Endocrinology and Metabolism 1994 842–846. (https://doi.org/10.1210/jcem.78.4.8157709)

    • Search Google Scholar
    • Export Citation
  • 63↑

    Cai WY, Alexander JM, Hedley-Whyte ET, Scheithauer BW, Jameson JL, Zervas NT, Klibanski A. ras mutations in human prolactinomas and pituitary carcinomas. Journal of Clinical Endocrinology and Metabolism 1994 89–93. (https://doi.org/10.1210/jcem.78.1.8288721)

    • Search Google Scholar
    • Export Citation
  • 64↑

    Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T & Ptak J et al.The genomic landscapes of human breast and colorectal cancers. Science 2007 1108–1113. (https://doi.org/10.1126/science.1145720)

    • Search Google Scholar
    • Export Citation
  • 65↑

    Tatsi C, Pankratz N, Lane J, Faucz FR, Hernandez-Ramirez LC, Keil M, Trivellin G, Chittiboina P, Mills JL & Stratakis CA et al.Large genomic aberrations in corticotropinomas are associated with greater aggressiveness. Journal of Clinical Endocrinology and Metabolism 2019 1792–1801. (https://doi.org/10.1210/jc.2018-02164)

    • Search Google Scholar
    • Export Citation
  • 66↑

    Megnis K, Peculis R, Rovite V, Laksa P, Niedra H, Belcere I, Caune O, Breiksa A, Nazarovs J & Stukens J et al.Evaluation of the possibility to detect circulating tumour DNA from pituitary adenoma. Frontiers in Endocrinology 2019 615. (https://doi.org/10.3389/fendo.2019.00615)

    • Search Google Scholar
    • Export Citation
  • 67↑

    Daly AF, Beckers A. Familial isolated pituitary adenomas (FIPA) and mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocrinology and Metabolism Clinics of North America 2015 19–25. (https://doi.org/10.1016/j.ecl.2014.10.002)

    • Search Google Scholar
    • Export Citation
  • 68↑

    Daly A, Cano DA, Venegas E, Petrossians P, Dios E, Castermans E, Flores-Martinez A, Bours V, Beckers A, Soto A. AIP and MEN1 mutations and AIP immunohistochemistry in pituitary adenomas in a tertiary referral center. Endocrine Connections 2019 8338–348. (https://doi.org/10.1530/EC-19-0027)

    • Search Google Scholar
    • Export Citation
  • 69↑

    Valdes Socin H, Poncin J, Stevens V, Stevenaert A, Beckers A. Familial isolated pituitary adenomas not linked to somatic MEN-1 mutations. Follow-up of 27 patients. Annales d’Endocrinologiel 2000 301.

    • Search Google Scholar
    • Export Citation
  • 70↑

    Daly AF, Jaffrain-Rea ML, Ciccarelli A, Valdes-Socin H, Rohmer V, Tamburrano G, Borson-Chazot C, Estour B, Ciccarelli E & Brue T et al.Clinical characterization of familial isolated pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 2006 3316–3323. (https://doi.org/10.1210/jc.2005-2671)

    • Search Google Scholar
    • Export Citation
  • 71↑

    Hernandez-Ramirez LC, Gabrovska P, Denes J, Stals K, Trivellin G, Tilley D, Ferrau F, Evanson J, Ellard S & Grossman AB et al.Landscape of familial isolated and young-onset pituitary adenomas: prospective diagnosis in AIP mutation carriers. Journal of Clinical Endocrinology and Metabolism 2015 E1242–E1254. (https://doi.org/10.1210/jc.2015-1869)

    • Search Google Scholar
    • Export Citation
  • 72↑

    Trivellin G, Korbonits M. AIP and its interacting partners. Journal of Endocrinology 2011 137–155. (https://doi.org/10.1530/JOE-11-0054)

    • Search Google Scholar
    • Export Citation
  • 73↑

    Ritvonen E, Pitkanen E, Karppinen A, Vehkavaara S, Demir H, Paetau A, Schalin-Jantti C, Karhu A. Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas. European Journal of Endocrinology 2017 243–252. (https://doi.org/10.1530/EJE-16-0620)

    • Search Google Scholar
    • Export Citation
  • 74↑

    Formosa R, Xuereb-Anastasi A, Vassallo J. Aip regulates cAMP signalling and GH secretion in GH3 cells. Endocrine-Related Cancer 2013 495–505. (https://doi.org/10.1530/ERC-13-0043)

    • Search Google Scholar
    • Export Citation
  • 75↑

    Tuominen I, Heliovaara E, Raitila A, Rautiainen MR, Mehine M, Katainen R, Donner I, Aittomaki V, Lehtonen HJ & Ahlsten M et al.AIP inactivation leads to pituitary tumorigenesis through defective Galphai-cAMP signaling. Oncogene 2015 1174–1184. (https://doi.org/10.1038/onc.2014.50)

    • Search Google Scholar
    • Export Citation
  • 76↑

    Schernthaner-Reiter MH, Trivellin G, Stratakis CA. Interaction of AIP with protein kinase A (cAMP-dependent protein kinase). Human Molecular Genetics 2018 272604–2613. (https://doi.org/10.1093/hmg/ddy166)

    • Search Google Scholar
    • Export Citation
  • 77↑

    Leontiou CA, Gueorguiev M, van der Spuy J, Quinton R, Lolli F, Hassan S, Chahal HS, Igreja SC, Jordan S & Rowe J et al.The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 2008 2390–2401. (https://doi.org/10.1210/jc.2007-2611)

    • Search Google Scholar
    • Export Citation
  • 78↑

    Cannavo S, Trimarchi F, Ferrau F. Acromegaly, genetic variants of the aryl hydrocarbon receptor pathway and environmental burden. Molecular and Cellular Endocrinology 2017 81–88. (https://doi.org/10.1016/j.mce.2016.12.019)

    • Search Google Scholar
    • Export Citation
  • 79↑

    Cannavo S, Ferrau F, Ragonese M, Curto L, Torre ML, Magistri M, Marchese A, Alibrandi A, Trimarchi F. Increased prevalence of acromegaly in a highly polluted area. European Journal of Endocrinology 2010 509–513. (https://doi.org/10.1530/EJE-10-0465)

    • Search Google Scholar
    • Export Citation
  • 80↑

    Cannavo S, Ragonese M, Puglisi S, Romeo PD, Torre ML, Alibrandi A, Scaroni C, Occhi G, Ceccato F & Regazzo D et al.Acromegaly is more severe in patients with AHR or AIP gene variants living in highly polluted areas. Journal of Clinical Endocrinology and Metabolism 2016 1872–1879. (https://doi.org/10.1210/jc.2015-4191)

    • Search Google Scholar
    • Export Citation
  • 81↑

    Bell DR, Poland A. Binding of aryl hydrocarbon receptor (AhR) to AhR-interacting protein. The role of hsp90. Journal of Biological Chemistry 2000 36407–36414. (https://doi.org/10.1074/jbc.M004236200)

    • Search Google Scholar
    • Export Citation
  • 82↑

    Lees MJ, Peet DJ, Whitelaw ML. Defining the role for XAP2 in stabilization of the dioxin receptor. Journal of Biological Chemistry 2003 35878–35888. (https://doi.org/10.1074/jbc.M302430200)

    • Search Google Scholar
    • Export Citation
  • 83↑

    Oesch-Bartlomowicz B, Huelster A, Wiss O, Antoniou-Lipfert P, Dietrich C, Arand M, Weiss C, Bockamp E, Oesch F. Aryl hydrocarbon receptor activation by cAMP vs. dioxin: divergent signaling pathways. PNAS 2005 9218–9223. (https://doi.org/10.1073/pnas.0503488102)

    • Search Google Scholar
    • Export Citation
  • 84↑

    Iacovazzo D, Hernandez-Ramirez LC, Korbonits M. Sporadic pituitary adenomas: the role of germline mutations and recommendations for genetic screening. Expert Review of Endocrinology and Metabolism 2017 143–153. (https://doi.org/10.1080/17446651.2017.1306439)

    • Search Google Scholar
    • Export Citation
  • 85↑

    Tichomirowa MA, Barlier A, Daly AF, Jaffrain-Rea ML, Ronchi C, Yaneva M, Urban JD, Petrossians P, Elenkova A & Tabarin A et al.High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas. European Journal of Endocrinology 2011 509–515. (https://doi.org/10.1530/EJE-11-0304)

    • Search Google Scholar
    • Export Citation
  • 86↑

    Preda V, Korbonits M, Cudlip S, Karavitaki N, Grossman AB. Low rate of germline AIP mutations in patients with apparently sporadic pituitary adenomas before the age of 40: a single-centre adult cohort. European Journal of Endocrinology 2014 659–666. (https://doi.org/10.1530/EJE-14-0426)

    • Search Google Scholar
    • Export Citation
  • 87↑

    Cai F, Zhang YD, Zhao X, Yang YK, Ma SH, Dai CX, Liu XH, Yao Y, Feng M & Wei JJ et al.Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort followed by LOH analysis. European Journal of Endocrinology 2013 867–884. (https://doi.org/10.1530/EJE-13-0442)

    • Search Google Scholar
    • Export Citation
  • 88↑

    Schofl C, Honegger J, Droste M, Grussendorf M, Finke R, Plockinger U, Berg C, Willenberg HS, Lammert A & Klingmuller D et al.Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study. Journal of Clinical Endocrinology and Metabolism 2014 E2789–E2793. (https://doi.org/10.1210/jc.2014-2094)

    • Search Google Scholar
    • Export Citation
  • 89↑

    Hernandez-Ramirez LC, Gabrovska P, Denes J, Stals K, Trivellin G, Tilley D, Ferrau F, Evanson J, Ellard S & Grossman AB et al.Landscape of familial isolated and young-onset pituitary adenomas: prospective diagnosis in AIP mutation carriers. Journal of Clinical Endocrinology and Metabolism 2015 E1242–E1254. (https://doi.org/10.1210/jc.2015-1869)

    • Search Google Scholar
    • Export Citation
  • 90↑

    Karaca Z, Taheri S, Tanriverdi F, Unluhizarci K, Kelestimur F. Prevalence of AIP mutations in a series of Turkish acromegalic patients: are synonymous AIP mutations relevant? Pituitary 2015 831–837. (https://doi.org/10.1007/s11102-015-0659-0)

    • Search Google Scholar
    • Export Citation
  • 91↑

    Ramirez-Renteria C, Hernandez-Ramirez LC, Portocarrero-Ortiz L, Vargas G, Melgar V, Espinosa E, Espinosa-de-Los-Monteros AL, Sosa E, Gonzalez B & Zuniga S et al.AIP mutations in young patients with acromegaly and the Tampico Giant: the Mexican experience. Endocrine 2016 402–411. (https://doi.org/10.1007/s12020-016-0930-9)

    • Search Google Scholar
    • Export Citation
  • 92↑

    De Sousa SMC, McCabe MJ, Wu K, Roscioli T, Gayevskiy V, Brook K, Rawlings L, Scott HS, Thompson TJ & Earls P et al.Germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours. European Journal of Endocrinology 2017 635–644. (https://doi.org/10.1530/EJE-16-0944)

    • Search Google Scholar
    • Export Citation
  • 93↑

    Tuncer FN, Dogansen SÇ, Serbest E, Tanrikulu S, Ekici Y, Bilgic B, Yarman S. Screening of AIP gene variations in a cohort of Turkish patients with young-onset sporadic hormone-secreting pituitary adenomas. Genetic Testing and Molecular Biomarkers 2018 22702–708. (https://doi.org/10.1089/gtmb.2018.0133)

    • Search Google Scholar
    • Export Citation
  • 94↑

    Cazabat L, Bouligand J, Salenave S, Bernier M, Gaillard S, Parker F, Young J, Guiochon-Mantel A, Chanson P. Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients. Journal of Clinical Endocrinology and Metabolism 2012 E663–E670. (https://doi.org/10.1210/jc.2011-2291)

    • Search Google Scholar
    • Export Citation
  • 95↑

    Cazabat L, Bouligand J, Chanson P. AIP mutation in pituitary adenomas. New England Journal of Medicine 2011 1973–1974; author reply 1974. (https://doi.org/10.1056/NEJMc1101859)

    • Search Google Scholar
    • Export Citation
  • 96↑

    Cuny T, Pertuit M, Sahnoun-Fathallah M, Daly A, Occhi G, Odou MF, Tabarin A, Nunes ML, Delemer B & Rohmer V et al.Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don’t forget MEN1 genetic analysis. European Journal of Endocrinology 2013 533–541. (https://doi.org/10.1530/EJE-12-0763)

    • Search Google Scholar
    • Export Citation
  • 97↑

    Stratakis CA, Tichomirowa MA, Boikos S, Azevedo MF, Lodish M, Martari M, Verma S, Daly AF, Raygada M & Keil MF et al.The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes. Clinical Genetics 2010 457–463. (https://doi.org/10.1111/j.1399-0004.2010.01406.x)

    • Search Google Scholar
    • Export Citation
  • 98↑

    Georgitsi M, De Menis E, Cannavo S, Makinen MJ, Tuppurainen K, Pauletto P, Curto L, Weil RJ, Paschke R & Zielinski G et al.Aryl hydrocarbon receptor interacting protein (AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas. Clinical Endocrinology 2008 621–627. (https://doi.org/10.1111/j.1365-2265.2008.03266.x)

    • Search Google Scholar
    • Export Citation
  • 99↑

    Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, Lecoq AL, Lecumberri B, Trivellin G, Salvatori R & Moraitis AG et al.Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocrine-Related Cancer 2015 745–757. (https://doi.org/10.1530/ERC-15-0320)

    • Search Google Scholar
    • Export Citation
  • 100↑

    Igreja S, Chahal HS, King P, Bolger GB, Srirangalingam U, Guasti L, Chapple JP, Trivellin G, Gueorguiev M & Guegan K et al.Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Human Mutation 2010 950–960. (https://doi.org/10.1002/humu.21292)

    • Search Google Scholar
    • Export Citation
  • 101↑

    Villa C, Lagonigro MS, Magri F, Koziak M, Jaffrain-Rea ML, Brauner R, Bouligand J, Junier MP, Di Rocco F & Sainte-Rose C et al.Hyperplasia-adenoma sequence in pituitary tumorigenesis related to aryl hydrocarbon receptor interacting protein gene mutation. Endocrine-Related Cancer 2011 347–356. (https://doi.org/10.1530/ERC-11-0059)

    • Search Google Scholar
    • Export Citation
  • 102↑

    Xekouki P, Mastroyiannis SA, Avgeropoulos D, de la Luz Sierra M, Trivellin G, Gourgari EA, Lyssikatos C, Quezado M, Patronas N & Kanaka-Gantenbein C et al.Familial pituitary apoplexy as the only presentation of a novel AIP mutation. Endocrine-Related Cancer 2013 L11–L14. (https://doi.org/10.1530/ERC-13-0218)

    • Search Google Scholar
    • Export Citation
  • 103↑

    Jaffrain-Rea ML, Angelini M, Gargano D, Tichomirowa MA, Daly AF, Vanbellinghen JF, D’Innocenzo E, Barlier A, Giangaspero F & Esposito V et al.Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications. Endocrine-Related Cancer 2009 1029–1043. (https://doi.org/10.1677/ERC-09-0094)

    • Search Google Scholar
    • Export Citation
  • 104↑

    Kasuki Jomori de Pinho L, Vieira Neto L, Armondi Wildemberg LE, Gasparetto EL, Marcondes J, de Almeida Nunes B, Takiya CM, Gadelha MR. Low aryl hydrocarbon receptor-interacting protein expression is a better marker of invasiveness in somatotropinomas than Ki-67 and p53. Neuroendocrinology 2011 39–48. (https://doi.org/10.1159/000322787)

    • Search Google Scholar
    • Export Citation
  • 105↑

    Daly AF, Tichomirowa MA, Petrossians P, Heliovaara E, Jaffrain-Rea ML, Barlier A, Naves LA, Ebeling T, Karhu A & Raappana A et al.Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. Journal of Clinical Endocrinology and Metabolism 2010 E373–E383. (https://doi.org/10.1210/jc.2009-2556)

    • Search Google Scholar
    • Export Citation
  • 106↑

    Oriola J, Lucas T, Halperin I, Mora M, Perales MJ, Alvarez-Escola C, Paz de de MN, Diaz Soto G, Salinas I & Julian MT et al.Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues. European Journal of Endocrinology 2013 9–13. (https://doi.org/10.1530/EJE-12-0457)

    • Search Google Scholar
    • Export Citation
  • 107↑

    Iacovazzo D, Carlsen E, Lugli F, Chiloiro S, Piacentini S, Bianchi A, Giampietro A, Mormando M, Clear AJ & Doglietto F et al.Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study. European Journal of Endocrinology 2016 241–250. (https://doi.org/10.1530/EJE-15-0832)

    • Search Google Scholar
    • Export Citation
  • 108↑

    Chahal HS, Trivellin G, Leontiou CA, Alband N, Fowkes RC, Tahir A, Igreja SC, Chapple JP, Jordan S & Lupp A et al.Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway. Journal of Clinical Endocrinology and Metabolism 2012 E1411–E1420. (https://doi.org/10.1210/jc.2012-1111)

    • Search Google Scholar
    • Export Citation
  • 109↑

    Jaffrain-Rea ML, Rotondi S, Turchi A, Occhi G, Barlier A, Peverelli E, Rostomyan L, Defilles C, Angelini M & Oliva MA et al.Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations. Endocrine-Related Cancer 2013 753–766. (https://doi.org/10.1530/ERC-12-0322)

    • Search Google Scholar
    • Export Citation
  • 110↑

    Kasuki L, Vieira Neto L, Wildemberg LE, Colli LM, de Castro M, Takiya CM, Gadelha MR. AIP expression in sporadic somatotropinomas is a predictor of the response to octreotide LAR therapy independent of SSTR2 expression. Endocrine-Related Cancer 2012 L25–L29. (https://doi.org/10.1530/ERC-12-0020)

    • Search Google Scholar
    • Export Citation
  • 111↑

    Theodoropoulou M, Tichomirowa MA, Sievers C, Yassouridis A, Arzberger T, Hougrand O, Deprez M, Daly AF, Petrossians P & Pagotto U et al.Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly. International Journal of Cancer 2009 2122–2126. (https://doi.org/10.1002/ijc.24602)

    • Search Google Scholar
    • Export Citation
  • 112↑

    Theodoropoulou M, Zhang J, Laupheimer S, Paez-Pereda M, Erneux C, Florio T, Pagotto U, Stalla GK. Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Research 2006 1576–1582. (https://doi.org/10.1158/0008-5472.CAN-05-1189)

    • Search Google Scholar
    • Export Citation
  • 113↑

    Birnbaumer L. Receptor-to-effector signaling through G proteins: roles for beta gamma dimers as well as alpha subunits. Cell 1992 1069–1072. (https://doi.org/10.1016/s0092-8674(05)80056-x)

    • Search Google Scholar
    • Export Citation
  • 114↑

    Zatelli MC, Piccin D, Tagliati F, Ambrosio MR, Margutti A, Padovani R, Scanarini M, Culler MD, degli Uberti EC. Somatostatin receptor subtype 1 selective activation in human growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas: effects on cell viability, GH, and PRL secretion. Journal of Clinical Endocrinology and Metabolism 2003 2797–2802.

    • Search Google Scholar
    • Export Citation
  • 115↑

    Joshi K, Daly AF, Beckers A, Zacharin M. Resistant paediatric somatotropinomas due to AIP mutations: role of pegvisomant. Hormone Research in Paediatrics 2018 196–202. (https://doi.org/10.1159/000488856)

    • Search Google Scholar
    • Export Citation
  • 116↑

    Daly A, Rostomyan L, Betea D, Bonneville JF, Villa C, Pellegata NS, Waser B, Reubi JC, Waeber Stephan C & Christ E et al.AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients. Endocrine Connections 2019 8367–377. (https://doi.org/10.1530/EC-19-0004)

    • Search Google Scholar
    • Export Citation
  • 117↑

    Beckers A, Rostomyan L, Daly AF. Overview of genetic testing in patients with pituitary adenomas. Annales d’Endocrinologie 2012 62–64. (https://doi.org/10.1016/j.ando.2012.03.028)

    • Search Google Scholar
    • Export Citation
  • 118↑

    Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P. Genetic mutations in sporadic pituitary adenomas – what to screen for? Nature Reviews: Endocrinology 2015 43–54. (https://doi.org/10.1038/nrendo.2014.181)

    • Search Google Scholar
    • Export Citation
  • 119↑

    Caimari F, Korbonits M. Novel genetic causes of pituitary adenomas. Clinical Cancer Research 2016 5030–5042. (https://doi.org/10.1158/1078-0432.CCR-16-0452)

    • Search Google Scholar
    • Export Citation
  • 120↑

    Caimari F, Hernandez-Ramirez LC, Dang MN, Gabrovska P, Iacovazzo D, Stals K, Ellard S, Korbonits M & International FIPA Consortium. Risk category system to identify pituitary adenoma patients with AIP mutations. Journal of Medical Genetics 2018 254–260. (https://doi.org/10.1136/jmedgenet-2017-104957)

    • Search Google Scholar
    • Export Citation
  • 121↑

    Daly AF, Vanbellinghen JF, Khoo SK, Jaffrain-Rea ML, Naves LA, Guitelman MA, Murat A, Emy P, Gimenez-Roqueplo AP & Tamburrano G et al.Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. Journal of Clinical Endocrinology and Metabolism 2007 1891–1896. (https://doi.org/10.1210/jc.2006-2513)

    • Search Google Scholar
    • Export Citation
  • 122↑

    Naves LA, Daly AF, Vanbellinghen JF, Casulari LA, Spilioti C, Magalhaes AV, Azevedo MF, Giacomini LA, Nascimento PP & Nunes RO et al.Variable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptor-interacting protein gene. European Journal of Endocrinology 2007 383–391. (https://doi.org/10.1530/EJE-07-0533)

    • Search Google Scholar
    • Export Citation
  • 123↑

    Beckers A, Petrossians P, Hanson J, Daly AF. The causes and consequences of pituitary gigantism. Nature Reviews: Endocrinology 2018 705–720. (https://doi.org/10.1038/s41574-018-0114-1)

    • Search Google Scholar
    • Export Citation
  • 124↑

    Chahal HS, Stals K, Unterlander M, Balding DJ, Thomas MG, Kumar AV, Besser GM, Atkinson AB, Morrison PJ & Howlett TA et al.AIP mutation in pituitary adenomas in the 18th century and today. New England Journal of Medicine 2011 43–50. (https://doi.org/10.1056/NEJMoa1008020)

    • Search Google Scholar
    • Export Citation
  • 125↑

    Beckers A, Lodish MB, Trivellin G, Rostomyan L, Lee M, Faucz FR, Yuan B, Choong CS, Caberg JH & Verrua E et al.X-linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocrine-Related Cancer 2015 353–367. (https://doi.org/10.1530/ERC-15-0038)

    • Search Google Scholar
    • Export Citation
  • 126↑

    Iacovazzo D, Caswell R, Bunce B, Jose S, Yuan B, Hernandez-Ramirez LC, Kapur S, Caimari F, Evanson J & Ferrau F et al.Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathologica Communications 2016 56. (https://doi.org/10.1186/s40478-016-0328-1)

    • Search Google Scholar
    • Export Citation
  • 127↑

    Rodd C, Millette M, Iacovazzo D, Stiles CE, Barry S, Evanson J, Albrecht S, Caswell R, Bunce B & Jose S et al.Somatic GPR101 duplication causing X-linked Acrogigantism (XLAG)-diagnosis and management. Journal of Clinical Endocrinology and Metabolism 2016 1927–1930. (https://doi.org/10.1210/jc.2015-4366)

    • Search Google Scholar
    • Export Citation
  • 128↑

    Naves LA, Daly AF, Dias LA, Yuan B, Zakir JC, Barra GB, Palmeira L, Villa C, Trivellin G & Junior AJ et al.Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome. Endocrine 2016 236–244. (https://doi.org/10.1007/s12020-015-0804-6)

    • Search Google Scholar
    • Export Citation
  • 129↑

    Daly AF, Lysy PA, Desfilles C, Rostomyan L, Mohamed A, Caberg JH, Raverot V, Castermans E, Marbaix E & Maiter D et al.GHRH excess and blockade in X-LAG syndrome. Endocrine-Related Cancer 2016 161–170. (https://doi.org/10.1530/ERC-15-0478)

    • Search Google Scholar
    • Export Citation
  • 130↑

    Daly AF, Yuan B, Fina F, Caberg JH, Trivellin G, Rostomyan L, de Herder WW, Naves LA, Metzger D & Cuny T et al.Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects. Endocrine-Related Cancer 2016 221–233. (https://doi.org/10.1530/ERC-16-0082)

    • Search Google Scholar
    • Export Citation
  • 131↑

    Trivellin G, Hernandez-Ramirez LC, Swan J, Stratakis CA. An orphan G-protein-coupled receptor causes human gigantism and/or acromegaly: molecular biology and clinical correlations. Best Practice and Research: Clinical Endocrinology and Metabolism 2018 125–140. (https://doi.org/10.1016/j.beem.2018.02.004)

    • Search Google Scholar
    • Export Citation
  • 132↑

    Beckers A, Rostomyan L, Potorac I, Beckers P, Daly AF & X-LAG. How did they grow so tall? Annales d’Endocrinologiel 2017 131–136.

  • 133↑

    Beckers A, Fernandes D, Fina F, Novak M, Abati A, Rostomyan L, Thiry A, Ouafik L, Pasture B & Pinhasi R et al.Paleogenetic study of ancient DNA suggestive of X-linked acrogigantism. Endocrine-Related Cancer 2017 L17–L20. (https://doi.org/10.1530/ERC-16-0558)

    • Search Google Scholar
    • Export Citation
  • 134↑

    Moran A, Asa SL, Kovacs K, Horvath E, Singer W, Sagman U, Reubi JC, Wilson CB, Larson R, Pescovitz OH. Gigantism due to pituitary mammosomatotroph hyperplasia. New England Journal of Medicine 1990 322–327. (https://doi.org/10.1056/NEJM199008023230507)

    • Search Google Scholar
    • Export Citation
  • 135↑

    Ferrau F, Romeo PD, Puglisi S, Ragonese M, Torre ML, Scaroni C, Occhi G, De Menis E, Arnaldi G & Trimarchi F et al.Analysis of GPR101 and AIP genes mutations in acromegaly: a multicentric study. Endocrine 2016 762–767. (https://doi.org/10.1007/s12020-016-0862-4)

    • Search Google Scholar
    • Export Citation
  • 136↑

    Matsumoto R, Izawa M, Fukuoka H, Iguchi G, Odake Y, Yoshida K, Bando H, Suda K, Nishizawa H & Takahashi M et al.Genetic and clinical characteristics of Japanese patients with sporadic somatotropinoma. Endocrine Journal 2016 953–963. (https://doi.org/10.1507/endocrj.EJ16-0075)

    • Search Google Scholar
    • Export Citation
  • 137↑

    Lecoq AL, Bouligand J, Hage M, Cazabat L, Salenave S, Linglart A, Young J, Guiochon-Mantel A, Chanson P, Kamenicky P. Very low frequency of germline GPR101 genetic variation and no biallelic defects with AIP in a large cohort of patients with sporadic pituitary adenomas. European Journal of Endocrinology 2016 523–530. (https://doi.org/10.1530/EJE-15-1044)

    • Search Google Scholar
    • Export Citation
  • 138↑

    Trivellin G, Correa RR, Batsis M, Faucz FR, Chittiboina P, Bjelobaba I, Larco DO, Quezado M, Daly AF & Stojilkovic SS et al.Screening for GPR101 defects in pediatric pituitary corticotropinomas. Endocrine-Related Cancer 2016 357–365. (https://doi.org/10.1530/ERC-16-0091)

    • Search Google Scholar
    • Export Citation
  • 139↑

    Wise-Oringer BK, Zanazzi GJ, Gordon RJ, Wardlaw SL, William C, Anyane-Yeboa K, Chung WK, Kohn B, Wisoff JH & David R et al.Familial X-linked Acrogigantism: postnatal outcomes and tumor pathology in a prenatally diagnosed infant and his mother. Journal of Clinical Endocrinology and Metabolism 2019 4667–4675. (https://doi.org/10.1210/jc.2019-00817)

    • Search Google Scholar
    • Export Citation
  • 140↑

    Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Best Practice and Research: Clinical Endocrinology and Metabolism 2010 355–370. (https://doi.org/10.1016/j.beem.2010.07.003)

    • Search Google Scholar
    • Export Citation
  • 141↑

    Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, Buisson N, De Witte K, Salandre J & Lenoir G et al.Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Human Molecular Genetics 1997 1177–1183. (https://doi.org/10.1093/hmg/6.7.1177)

    • Search Google Scholar
    • Export Citation
  • 142↑

    Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA & Liotta LA et al.Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997 404–407. (https://doi.org/10.1126/science.276.5311.404)

    • Search Google Scholar
    • Export Citation
  • 143↑

    Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology 2014 2–15. (https://doi.org/10.1016/j.mce.2013.08.002)

    • Search Google Scholar
    • Export Citation
  • 144↑

    Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F & Brandi ML et al.Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). Journal of Clinical Endocrinology and Metabolism 2012 2990–3011. (https://doi.org/10.1210/jc.2012-1230)

    • Search Google Scholar
    • Export Citation
  • 145↑

    Beckers A, Betea D, Valdes Socin H, Stevenaert A. The treatment of sporadic versus MEN1-related pituitary adenomas. Journal of Internal Medicine 2003 599–605. (https://doi.org/10.1046/j.1365-2796.2003.01164.x)

    • Search Google Scholar
    • Export Citation
  • 146↑

    Verges B, Boureille F, Goudet P, Murat A, Beckers A, Sassolas G, Cougard P, Chambe B, Montvernay C, Calender A. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. Journal of Clinical Endocrinology and Metabolism 2002 457–465. (https://doi.org/10.1210/jcem.87.2.8145)

    • Search Google Scholar
    • Export Citation
  • 147↑

    Marini F, Giusti F, Fossi C, Cioppi F, Cianferotti L, Masi L, Boaretto F, Zovato S, Cetani F & Colao A et al.Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database. Endocrine 2018 215–233. (https://doi.org/10.1007/s12020-018-1566-8)

    • Search Google Scholar
    • Export Citation
  • 148↑

    de Laat JM, Dekkers OM, Pieterman CR, Kluijfhout WP, Hermus AR, Pereira AM, van der Horst-Schrivers AN, Drent ML, Bisschop PH & Havekes B et al.Long-term natural course of pituitary tumors in patients With MEN1: results from the DutchMEN1 Study Group (DMSG). Journal of Clinical Endocrinology and Metabolism 2015 3288–3296. (https://doi.org/10.1210/JC.2015-2015)

    • Search Google Scholar
    • Export Citation
  • 149↑

    Goudet P, Bonithon-Kopp C, Murat A, Ruszniewski P, Niccoli P, Menegaux F, Chabrier G, Borson-Chazot F, Tabarin A & Bouchard P et al.Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d’etude des Tumeurs Endocrines. European Journal of Endocrinology 2011 97–105. (https://doi.org/10.1530/EJE-10-0950)

    • Search Google Scholar
    • Export Citation
  • 150↑

    Sakurai A, Suzuki S, Kosugi S, Okamoto T, Uchino S, Miya A, Imai T, Kaji H, Komoto I & Miura D et al.Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database. Clinical Endocrinology 2012 533–539. (https://doi.org/10.1111/j.1365-2265.2011.04227.x)

    • Search Google Scholar
    • Export Citation
  • 151↑

    Giusti F, Cianferotti L, Boaretto F, Cetani F, Cioppi F, Colao A, Davi MV, Faggiano A, Fanciulli G & Ferolla P et al.Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database. Endocrine 2017 349–359. (https://doi.org/10.1007/s12020-017-1234-4)

    • Search Google Scholar
    • Export Citation
  • 152↑

    Trouillas J, Labat-Moleur F, Sturm N, Kujas M, Heymann MF, Figarella-Branger D, Patey M, Mazucca M, Decullier E & Verges B et al.Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. American Journal of Surgical Pathology 2008 534–543. (https://doi.org/10.1097/PAS.0b013e31815ade45)

    • Search Google Scholar
    • Export Citation
  • 153↑

    Sergeant C, Jublanc C, Leclercq D, Boch AL, Bielle F, Raverot G, Daly AF, Trouillas J, Villa C. Transdifferentiation of neuroendocrine cells: gangliocytoma associated with two pituitary adenomas of different lineage in MEN1. American Journal of Surgical Pathology 2017 849–853. (https://doi.org/10.1097/PAS.0000000000000803)

    • Search Google Scholar
    • Export Citation
  • 154↑

    Magri F, Villa C, Locatelli D, Scagnelli P, Lagonigro MS, Morbini P, Castellano M, Gabellieri E, Rotondi M & Solcia E et al.Prevalence of double pituitary adenomas in a surgical series: clinical, histological and genetic features. Journal of Endocrinological Investigation 2010 325–331. (https://doi.org/10.1007/BF03346594)

    • Search Google Scholar
    • Export Citation
  • 155↑

    Uraki S, Ariyasu H, Doi A, Furuta H, Nishi M, Usui T, Yamaue H, Akamizu T. Hypersecretion of ACTH and PRL from pituitary adenoma in MEN1, adequately managed by medical therapy. Endocrinology, Diabetes and Metabolism Case Reports 2017 2017 Article ID: 17-0027. (https://doi.org/10.1530/EDM-17-0027)

    • Search Google Scholar
    • Export Citation
  • 156↑

    Scheithauer BW, Laws ER Jr, Kovacs K, Horvath E, Randall RV, Carney JA. Pituitary adenomas of the multiple endocrine neoplasia type I syndrome. Seminars in Diagnostic Pathology 1987 205–211.

    • Search Google Scholar
    • Export Citation
  • 157↑

    Marques NV, Kasuki L, Coelho MC, Lima CHA, Wildemberg LE, Gadelha MR. Frequency of familial pituitary adenoma syndromes among patients with functioning pituitary adenomas in a reference outpatient clinic. Journal of Endocrinological Investigation 2017 1381–1387. (https://doi.org/10.1007/s40618-017-0725-8)

    • Search Google Scholar
    • Export Citation
  • 158↑

    Stratakis CA, Schussheim DH, Freedman SM, Keil MF, Pack SD, Agarwal SK, Skarulis MC, Weil RJ, Lubensky IA & Zhuang Z et al.Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1. Journal of Clinical Endocrinology and Metabolism 2000 4776–4780. (https://doi.org/10.1210/jcem.85.12.7064)

    • Search Google Scholar
    • Export Citation
  • 159↑

    Subasinghe CJ, Somasundaram N, Sivatharshya P, Ranasinghe LD,